- Email: [email protected]
Restorative retinal laser therapy: Present state and future directions
Accepted Manuscript RESTORATIVE RETINAL LASER THERAPY: Present state and future directions. Jay Chhablani, Young Jung Roh, Andrew I. Jobling, Erica L. Fletcher, Jia Jia Lek, Pooja Bansal, Robyn Guymer, Jeffrey K. Luttrull PII:
S0039-6257(17)30166-2
DOI:
10.1016/j.survophthal.2017.09.008
Reference:
SOP 6757
To appear in:
Survey of Ophthalmology
Received Date: 20 May 2017 Revised Date:
13 September 2017
Accepted Date: 22 September 2017
Please cite this article as: Chhablani J, Roh YJ, Jobling AI, Fletcher EL, Lek JJ, Bansal P, Guymer R, Luttrull JK, RESTORATIVE RETINAL LASER THERAPY: Present state and future directions., Survey of Ophthalmology (2017), doi: 10.1016/j.survophthal.2017.09.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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RESTORATIVE RETINAL LASER THERAPY: Present state and future directions.
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Jay Chhablani,1 Young Jung Roh, 2 Andrew I. Jobling,3 Erica L. Fletcher,3 Jia Jia Lek, 4 Pooja Bansal,5 Robyn Guymer,4 Jeffrey K
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Luttrull, 7,8
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1. L.V.Prasad Eye Institute, Kallam Anji Reddy Campus, Banjara Hills, HYDERABAD - 500 034
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2. Department of Ophthalmology and Visual Science, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic
University of Korea, Seoul, Korea 10, 63-ro, Yeongdeungpo-gu, Seoul 150-713, Korea e-mail: [email protected]
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3. Department of Anatomy and Neuroscience. The University of Melbourne, Parkville 3010 Victoria, Australia.
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4. Centre for Eye Research Australia, University of Melbourne, Department of Surgery (Ophthalmology), Royal Victorian Eye
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110 029, India
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5. Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi -
6. Ventura County Retina Vitreous Medical Group, 3160 Telegraph Road, Suite 230, Ventura, California 93003
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and Ear Hospital, Victoria, Australia
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Corresponding author: Jeffrey K Luttrull, MD. Ventura County Retina Vitreous Medical Group, 3160 Telegraph Road, Suite 230,
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Ventura, California 93003. Ph 805.650.0664. Fax 805.650.0865. Email [email protected] Web
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www.venturacountyretina.com
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ABSTRACT
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Because of complications and side effects, conventional laser therapy has taken a back seat to drugs in the treatment of
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macular diseases. Despite this, research on new laser modalities remains active. In particular, various approaches are being
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pursued to preserve and improve retinal structure and function. These include micropulsing, various exposure titration algorithms
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and real-time temperature feedback control of short pulse continuous wave lasers, and ultra-short pulse nanosecond lasers.
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Some of these approaches are at the pre-clinical stage of development, while others are available for clinical use. Cell biology is
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providing important insights into the mechanisms of action of retinal laser treatment. We outline the technological bases of
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current laser platforms, their basic science, therapeutic concepts, clinical experience, and future directions for retinal laser
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treatment.
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KEY WORDS: Laser photocoagulation; Subthreshold Laser; Micropulse Laser; Retinal Laser; Microsecond Laser; Panretinal
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Photocoagulation; PASCAL; NAVILAS; Pattern Scanning Lasers; Nanosecond Laser; Selective Retina Therapy; Endpoint
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Management; 2RT
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INTRODUCTION
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Laser photocoagulation has been used for decades to treat a number of common retinal disorders. These include diabetic
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macular edema (DME), proliferative diabetic retinopathy (PDR), macular edema secondary to branch retinal vein occlusion
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(BRVO), retinal ischemia from vasculitis, retinal vascular occlusion, central serous chorioretinopathy (CSR), ablation of age-
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related choroidal neovascularization (NAMD), and retinopexy for retinal tears. The advent of anti-vascular endothelial growth
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factor (anti-VEGF) therapy saw the role of laser therapy diminish. This occurred for two principal reasons: the risks and adverse
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treatment effects associated with conventional photocoagulation and the remarkable effectiveness of the new pharmacologic
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agents. Despite this, considerable progress has been made in developing new laser systems and modes of treatment to improve
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their safety and effectiveness and increase their clinical utility. Following a brief review of laser principles and technology, each
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current retinal laser platform and treatment approach will be discussed. These approaches are at times at odds. While some
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advocate treatment sublethal to the retina, others employ selective retinal damage; however, the commonalities are also notable.
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All seek to eliminate or reduce retinal damage, to expand treatment indications, and to improve patient outcomes by avoiding
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conventional retinal photocoagulation.
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REVIEW OF RETINAL LASERS AND THEIR EFFECTS
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Conventional continuous-wave (CW) laser retinal photocoagulation (RPC) is a photothermal destructive therapy where the
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photoreceptor/retinal pigment epithelium (RPE)-choriocapillaris complex is coagulated with visible burns, with elevation in tissue
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temperature mediating the therapeutic effect. The heat created by RPC spreads outward from the burn site in the RPE and/ or
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choroid. The ‘‘grayish-white’’ endpoint of RPC signifies that the thermal wave has reached the overlying neurosensory retina with
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a temperature high enough to coagulate proteins in the naturally transparent neural retina, making it opaque by scattering light.
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(74) Becaue of the intensity of retinal irradiation, RPC may be painful despite use of topical anesthetic drops, requiring local
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anesthesia. Alternatively, treatment may be divided into stages over an extended time to minimize treatment-related pain and
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postoperative inflammation. Because RPC typical employs visible light wavelengths, RPC often produces uncomfortable flashes
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of light as laser spots are applied. Inflammation resulting from photocoaulative tissue destruction may cause reduction in visual
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acuity, usually transient, following RPC. Such factors may increase patient anxiety and reduce compliance with the prescribed
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treatment regimen. All complications and adverse treatment effects of RPC are attributable to laser-induced retinal damage
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(LIRD). These include progressive scar expansion, visual field defects, alterations in color vision, reduced contrast sensitivity,
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subretinal fibrosis, and choroidal neovascularisation. (26, 82, 90)
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CURRENT RETINAL LASER MODES
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Laser is an acronym for light amplification by stimulated emission of radiation. All lasers are comprised of three essential
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components: a lasing material, a pump source to introduce energy into the lasing material, and an optical cavity with reflectors
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for light amplification. Population inversion occurs when energy from the pump source is introduced into the lasing material,
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which excites electrons in the lasing material’s atoms and causes them to go from a steady, low-energy state to an unstable,
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higher-energy level. (83) Decay (the return of electrons to the steady state energy level) releases photons of the wavelength of
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the energy transition that have the ability to travel in phase in the same direction. Amplification of this coherent radiation occurs
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as photons travel back and forth in phase in the optical cavity through the lasing material between a total reflecting mirror and a
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partial reflecting mirror. When sufficient energy has built up, this laser light may be released through the partially reflecting mirror
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and directed toward the retina, effecting treatment.
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Some important definitions are:
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Power - The rate at which energy is emitted from a laser.
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Population inversion: The state present within the laser optical cavity (resonator) where more atoms exist in unstable high-energy
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levels than their normal resting energy levels.
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Pulse: The brief span of time for which the focused and scanned laser beam interacts with a given point on the target (usually
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from milliseconds to nanoseconds)
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Q-Switch: An optical device that controls the storage or release of laser energy from a laser optical cavity. Q-switching is a
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means of creating very short pulses (5-100 ns) with extremely high peak powers. Q stands for quality.
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Titration: Adjustment of laser dose based on patient response. Dosages are traditionally adjusted by the operating surgeon by
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directly visualizing retinal laser effects on the retina until the desired level of intensity is achieved.
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Duty cycle : “Pulsed” lasers apply laser exposure in trains of short burst, rather than the continuous beam of conventional lasers.
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The duty cycle is defined as the length of time of “power on” divided by the total time the laser is used. For example, the duty
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cycle of a conventional laser is 100% because, during the laser exposure, the laser beam is on continuously. A 5% duty cycled
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pulsed laser means that each burst of energy released (a “micropulse”) is “on” for 100 µs followed by 1900 µs in the “off” mode.
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Lasers can be used in distinct modes of operation depending on duration of laser emission. The most important are
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continuous wave (CW operation) refers to a laser that produces a continuous output beam, causing a rapid temperature rise.
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Quasi-continuous-wave operation (quasi-CW operation) is when the pump source is switched on only for short time intervals to
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minimize heat transfer.
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Gain-switched operation: gain switching means that the pump source is turned out only for very short time intervals in order to
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obtain short pulses.
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Q-switched operation: In a Q-switched laser, the population inversion is allowed to build up by introducing loss inside the
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resonator, which exceeds the gain of the medium. The intracavity losses are modulated, allowing lasing to begin which rapidly
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obtains the stored energy in the gain medium so that the laser emits energetic pulses.
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Mode-locked operation: Mode-locking is an optical technique by which a laser can be made to produce pulses of extremely short
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duration, on the order of picoseconds (10−12 s) or femtoseconds (10−15 s). Mode-locked lasers employ resonant modes of the
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optical cavity which can affect the characteristics of the output beam. When the phases of different frequency modes are
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synchronized, or "locked”, the different modes will interfere with one another to generate a beat effect. The resultant laser output
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is regularly spaced pulsations. A mode-locked laser can deliver higher peak powers than the same laser operating in the Q-
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Evolution of Retinal Laser Photocoagulation
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The era of photocoagulation was born in 1956 when Meyer-Schwickerath and Littman worked with Zeiss to design the first
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Xenon-arc coagulator. (61) In 1960, Maimann then invented the ruby laser, (58) a solid-state laser with wavelength of 694 nm
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emitted short pulses (less than 1 millisecond). The ruby laser provided a more controlled delivery of energy, allowing
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ophthalmologists to manipulate and more precisely target light beams, creating small chorioretinal scars and reducing the risk of
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damage to surrounding tissues compared to the Xenon arc lamp. Though this wavelength transmits well through ocular media
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and is absorbed efficiently by the retinal pigment epithelium and choroid, it was poorly absorbed by blood, preventing effective
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treatment of vascular lesions.
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Discovery of the Argon laser in 1964 by Bridges provided a new tool with emission in the blue (488-nm) and green (514-
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nm) range of the spectrum. (8) Subsequently, Krypton red and tuneable dye gas lasers included yellow and orange wavelengths.
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Eventually, shorter wavelengths in the blue range were abandoned to reduce damage to the neurosensory retina. Gas lasers
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suffered from significant impracticalities including large size, the need for water cooling, high voltage electric power, and gradual
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degradation and power loss. Today, the more commonly used frequency doubled Nd:YAG and diode lasers use solid-state
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platforms that utilize crystals and semiconductors, respectively. These current lasers are compact, portable, highly reliable, and
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long lasting. (83)
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THE MECHANISM OF RETINAL LASER TREATMENT
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Historically, the 4 main hypotheses offered to explain the mechanism of retinal laser action accepted LIRD as the necessary and
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sufficient cause of the therapeutic effects. These included reduction in oxygen consumption and thus metabolic stress by thermal
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destruction of the retina and / or retinal photoreceptors; photoablative debulking of pathologic retina by RPC, improved choroidal-
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retinal oxygenation by photocoagulation-induced retinal thinning, and/or retinal heat-shock protein (HSP) activation. (54) Despite
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consideration of these hypotheses for over 50 years, none was proven. Shorter wavelength lasers (below 550nm) were found to
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produce photochemical damage to the neurosensory retina without improving outcomes. Thus, the therapeutic effects of retinal
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laser treatment appeared to be entirely thermal in origin; however, it was not until demonstration of clinically effective retinal laser
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treatment designed to be reliably sublethal to the retina that the long-held belief in the therapeutic necessity of LIRD was called
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into question. This effectively eliminated the theories of retinal laser action that invoked the need for photocoagulation. Of the 4
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primary theories of retinal laser action, only thermal - but sublethal - retinal HSP activation remained. (4, 11, 14, 24, 26, 31, 44,
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47, 48, 51, 52, 54, 59, 62, 74, 77, 82, 90, 98)
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In vitro testing has subsequently confirmed thermal laser induced HSP activation in the retina surviving laser exposure as the
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likely key trigger of the therapeutic response. This demonstrated translational replacement of the HSPs used in the stress
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response in the specific patterns predicted and depicted by Luttrull and Dorin in 2012. (11, 31, 49, 87) Application of scaling law
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analysis to the biophysics of laser-retinal interactions indicates a strong association between thermal laser effects and HSP
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activation as the initiating step in a cascade of reparative phenomena improving RPE function, retinal autoregulation, reparative
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acute inflammation, reduced markers of chronic inflammation, and immunomodulation. (11, 25) In a recent murine model,
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micropulsed 810nm laser was applied at sublethal intensity to the RPE, producing increases in mRNAs for Hspa1a, Hsp90aa1,
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Cryab; Hif1a, Cxcl12, Hspa1a Ccl-2, Il1-β, IFN-γ and Il-6 between 2 to 24 hours post treatment in the RPE-choroid. (11) One and
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two weeks following sublethal micropulse treatment of the RPE one eye, recruitment of bone-marrow stem cells to the RPE of
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both eyes was documented, showing that sublethal thermal photostimulation of the retinal pigment epithelium can produce a
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systemic immunologic response. (11) This latter observation may account for the common observation of bilateral improvements
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after unilateral laser treatment. (27) In sum, all therapeutic retinal laser effects are in fact “subthreshold” and derived from retina
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affected, but not killed, by retinal laser exposure. (49)
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The biophysics of various modes of retinal laser delivery dictates four basic classes of potentially therapeutic retinal laser effects. Each has been well demonstrated and documented clinically and in laboratory studies:
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1. Retinal photocoagulation (RPC): In RPC, the targeted tissue is thermally destroyed by CW or high-duty cycle micropulsed
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laser. At the site of laser application, retinal function is lost, and the destroyed tissue does not participate in the therapeutic
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effect. Instead, collateral heating of surviving tissue at the margins of the RPC lesion indirectly produces the desired therapeutic
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effects, as well as healing the laser-induced retinal damage.
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2. Selective retinal ablation (SRA): Short and ultra-short pulsed CW lasers generated by gain-locked, Q-switched, and mode-
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locked devices. The Arrhenius integral for cell death is exceeded before the threshold of the integral for HSP activation is
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reached. The RPE is selectively ablated without significant collateral thermal or physical effects. Thus, like RPC, the therapeutic
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effect of SRA is produced indirectly by the healing response and inflammation that occurs in response to the RPE ablation as
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cells adjacent to the wound respond by sliding to fill and repair the laser-induced RPE defect. Unlike RPC, there is effectively no
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therapeutic contribution from sublethal stimulation of tissue adjacent to the laser spot.
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3. Simple retinal photostimulation (SRP): CW laser treatment at very low power can be used to stimulate the RPE sublethally.
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Thus, in SPR therapeutic HSP activation is direct. Because the therapeutic window of CW laser is extremely narrow (10mW) and
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human RPE pigment heterogeneity is high (compared to rabbits and mice), safe, effective, predictable, and reliably sublethal
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SRP is difficult. Currently, attempts at algorithmic titration termed “end-point management” and real-time photoacoustic tissue
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temperature modulation seek to improve the safety and effectiveness of CW laser by improving targeting of the narrow
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therapeutic window. (46, 47, 76, 77) Because the safe temperature rise of sublethal CW laser is relatively gradual (1000 C / sec),
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various studies suggest it may not be an especially efficient stimulator of RPE HSPs. (13, 29, 45, 64, 65)
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4. Amplified retinal photostimulation (ARP): Low-duty cycle micropulsed laser is used to directly stimulate RPE HSP activation
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sublethally. This mode is exemplified by low-intensity / high-density subthreshold diode micropulse laser (“SDM”). Because the
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therapeutic range (TR, the range between the initiation of a biologic effect to the 50/50 burn risk threshold) of SDM is broad (over
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3 Watts currently; increasable to 25 Watts or more) treatment titration (associated with LIRD in all published studies) is
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unnecessary. Because the known maximum variation of human RPE pigment density is 1.5 – 2.0x “normal”, all patients fall
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within the broad therapeutic range of ARP. (25, 46, 47, 49, 51, 54, 56, 87, 88) Thus, ARP can be performed with fixed laser
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parameters known to be both safe and effective. Absent LIRD and its associated inflammation and loss of retinal function, there
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is a complete absence of known adverse treatment effects, prompt (within 24 hours) improvements in visual function and
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electrophysiology, and long-term clinical benefits in all reported applications. The ARP / SDM treatment strategy of “low-intensity
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/ high-density” treatment application echoes the Early Treatment of Diabetic Retinopathy Study (EDTRS) finding that increased
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treatment intensity (and LIRD) is associated with poorer visual results and increased adverse treatment effects, while increased
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treatment density is associated with improved anatomic results. (6, 14, 21, 24, 43, 44, 51, 54, 56, 59, 67, 74, 84, 85, 91, 92). The
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safety of ARP allows confluent (highest-density) treatment application, maximizing visual and anatomic results. (51) For
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example, ARP, as transfoveal SDM, has been reported to significantly improve both visual acuity and macular thickness with
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eyes with center-involving DME and excellent (20/40 or better) pre-treatment visual acuity, without adverse treatment effects.
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(44, 54) The abrupt but sublethal temperature changes of the micropulsed laser (100,0000 C/ sec) may be especially efficient
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triggers of RPE HSP activation (thus, “amplified” retinal photostimulation) capable of increasing the effectiveness of HSP
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activation by magnitudes compared to SRP and broadening the therapeutic range by lowering the HSP activation threshold. (19,
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25, 48)
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We will now examine the above concepts by reviewing each current retinal laser platform, its clinical application, and current
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laboratory research. Thereafter, an informed look at the future of retinal laser treatment will be offered.
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MICROPULSE LASER PHOTOCOAGULATION
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In 1990, Pankratov reported development of a new laser modality designed to deliver laser energy in short pulses
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(“micropulses”) rather than as a continuous wave. (68) Micropulse technology is a laser delivery method that added a new
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dimension of control over laser output, facilitating tissue-sparing applications. Unlike conventional continuous wave laser
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photocoagulation, micropulse technology finely controls thermal elevation by “chopping” a CW beam into an envelope of
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repetitive short pulses. Repetitive short “micro” pulses can produce higher peak tissue temperatures and more abrupt tissue
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temperature changes (100,0000 C/sec) compared to CW lasers (1000 C/sec), while pulse spacing permits the tissue to cool
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between pulses, minimizing heat buildup. By shortening laser pulses, the temperature rise occurs with increasing selectivity in
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the RPE. (19) The main determinant of average tissue temperature rise is the duty cycle (the frequency of the train of
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micropulses), dictating the length of time between pulses. (19, 56) The lower the duty cycle, the longer the off time between
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pulses (lower repetition rate) and the less heat build-up. If the off time exceeds the thermal relaxation time of RPE melanin (the
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target molecule), the average tissue temperature rise in the RPE during micropulsed laser application can be maintained below
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levels lethal to the cell. Clinical studies and computer modeling have demonstrated that treatment safety is maximized by use of
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5% or lower duty cycles.
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determinant of laser efficacy is peak temperature. By minimizing average tissue temperature heat buildup with a low duty cycle,
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micropulsing can produce higher sublethal peak temperatures than CW lasers. Thus, micropulsing (MP) is both safer and more
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effective. (19, 25, 56) Numerous studies have shown MP is effective at sublethal irradiation levels, offering a tissue-sparing
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Higher duty cycles rapidly take on the clinical characteristics of CW lasers. Another important
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solution for the treatment of various retinal diseases. Treatment is painless, requiring only topical anesthesia. Following MP laser
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patients may report improved visual function within hours of treatment, and the risk of treatment-associated visual loss from
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LIRD and resultant inflammation can be avoided. (19, 51, 54, 56)
CLINICAL APPLICATIONS OF MICROPULSED LASERS
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Diabetic macular edema
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The application and development of subthreshold / sublethal retinal laser treatment has centered on the treatment of diabetic macular edema (DME). The ETDRS showed that increased treatment intensity was associated with more adverse
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treatment effect,s, that increased treatment density improved clinical results, that grid treatment was as effective as focal
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treatment; and that the location and extent of macular angiographic leakage did not correlate with clinical outcomes. (74) With
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this knowledge, practitioners began to move to less damaging retinal laser treatment, primarily by reducing treatment intensity.
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LIRD, however, was universally believed to be essential to obtain a therapeutic effect, and the risks and limitations of treatment
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persisted. (21, 24, 59, 62)
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In 1997, Friberg and Karatza first reported clinical application of MP 810nm diode laser therapy for DME. Since LIRD was still
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presumed to be necessary to achieve effective therapy, micropulsing was used to reduce (“invisible”), but maintain, LIRD. This
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was done by use of high duty cycles (15% or more) to enhance the photocoagulative potential of the MP 810nm laser. (19, 21,
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24, 62, 67, 84) In 2004, Laursen reported use of the 810nm laser using a lower 5% duty cycle; (43) however, long exposure
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durations (3.0 seconds) were employed, again with the intent of causing LIRD. Thus, the presumption that LIRD was essential
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for a therapuetic effect perpetuated the limitations and adverse treatment effects of associated with conventional retinal
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photocoagulation.
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Year 2000 marked a significant change in the conception and application of retinal laser therapy. (51) For the first time retinal
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laser treatment was performed with the intent of preventing LIRD; that is, treatment sublethal to the RPE. This was done by
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exploiting attributes unique to the MP laser (MPL). Rather than using high duty cycles or long exposures to cause LIRD, a low
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(5%) duty cycle was employed with new parameters intended to avoid retinal damage. (56) The safety afforded by avoidance of
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LIRD allowed a second, simultaneous and critical innovation: complete and contigous laser coverage of all areas of retinal
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pathology. (51) By so doing, broad recruitment of the target tissue and primary disease mediator – the RPE – was achieved,
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maximizing therapeutic effects. With this new approach, called “low-intensity / high-density subthreshold diode micropulse laser”
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(SDM), effective and reliably sublethal retinal laser treatment could be done without any LIRD or adverse treatment effects. The
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SDM strategy of high-density sublethal retinal laser application defines modern retinal laser therapy.(6, 14, 41, 49, 51, 84)
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Since Friberg, many studies have reported the efficacy of MPL for DME (Table 1). Gradually, the intent of causing LIRD via high
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duty cycles and use of conventional application techniques has been replaced by the low-intensity (sublethal) / high-density
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(confluent treatment of broad areas) treatment paradigm. (56) Studies of MPL for DME show that increased treatment density
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maximizes macular thickness reduction, while avoidance of LIRD maximizes visual acuity improvement. (14, 44, 51) Controversy
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exists regarding use of MPL as a first line treatment, or secondary to drug therapy; however, there is wide agreement on two key
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points: the effectiveness of micropulse laser as primary monotherapy in eyes with macular thickening < 400um and the
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superiority visual results of MPL to conventional laser techniques such as modified EDTRS photocoagulation. (6, 14, 44) While
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Sivaprasad and associates reported a 28% recurrence rate of DME within 3 years of initial MPL treatment, avoidance of LIRD
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makes it possible to repeat treatment as necessary to prevent visual loss. (83) The reliable safety of SDM permits early
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treatment of DME, including transfoveal treatment for center-involving DME with good visual acuity, reducing the risk of visual
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loss, and minimizing the need for intensive and expensive intravitreal drug therapy. (51, 54, 56, 91) (Figure 1)
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Proliferative diabetic retinopathy
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Moorman and Hamilton used high-duty cycle MPL as “minimal intensity” panretinal photocoagulation (PRP) for proliferative
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diabetic retinopathy (PDR), with the goal of maintaining the LIRD thought at the time necessary for effective therapy, while
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reducing the severity of photocoagulative retinal damage and associated adverse treatment effects. In 10/13 eyes treated, they
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noted regression of neovascularization. (62) The only report of sublethal panretinal micropulse laser (SDM PRP) to date
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described 99 eyes (61 with PDR and 38 severe non-proliferative DR) of 69 consecutive patients treated between 2000-2003,
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followed for a median of 12 months. (52) Overall VA remained unchanged, but the proportion of eyes with excellent VA (20/30 or
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better) increased from 39% to 48%. Because of large peripheral retinal laser spot sizes (1mm) and 810nm diode laser power
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limitations (2.0 Watt maximum), a 15% duty cycle was employed to achieve a therapeutic irradiance. Despite the still low
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irradiance levels, equivalent to just 18x American National Standards Institute “Maximal Permissible Exposure” levels (ANSI
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MPE), treatment was found to be effective and comparable to conventional PRP. (51, 56) Despite the high duty cycle, no LIRD
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was observed. SDM PRP was performed in a single session with topical anesthesia, and no patient reported postoperative pain
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or loss of visual acuity, accommodation, night vision, or visual field. In the absence of LIRD, there was no postoperative
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inflammation, and no eye demonstrated development or worsening of macular edema postoperatively. The absence of
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inflammation was credited with a notably quiet postoperative clinical course, with minimal preretinal fibrosis and membrane
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contraction and no apparent inducement of posterior vitreous detachment. No eye progressed to a surgical traction retinal
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detachment or neovascular glaucoma. Only 3 of 38 eyes with severe non-proliferative diabetic retinopathy (7.9%) progressed to
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PDR. Compared to the expected annual rate of 50%, this reduction in DR progression was significant (p=0.0001). (52) Table 2
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shows the summary of studies evaluating micropulse laser in PDR. (Figure 2-4)
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Central serous chorioretinopathy
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MPL was first reported for the treatment of CSR by Lanzetta, et al, in 2003. (42) Since then, over 30 studies of MPL for CSR
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have been published (www.ncbi.nlm.nih.gov/pubmed/), including retrospective and randomized controlled studies of various
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sizes employing a variety of different laser wavelengths, treatment parameters, treatment protocols, and patient populations. (57,
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60) Despite such heterogeniety, in all studies MPL for CSR has been found to be effective: comparable to half-fluence
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photodynamic therapy, superior to anti-VEGF therapy, and safe. Comparison of these studies suggests that, reflecting the prior
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discussion, the effectiveness of MPL for CSR parallels treatment density, while safety parallels treatment intensity. The safety of
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the SDM strategy (low-duty cycle with fixed treatment parameters) allows reliably safe treatment of subfoveal leaks, early
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treatment, and repeat treatment should clinical needs dictate. (57, 60) Nearing completion is the PLACE trial (clinicaltrials.gov:
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NCT01797861), a randomized prospective clinical trial in the Netherlands comparing half-dose verteporfin photodynamic therapy
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with MPL for central serous choroiretinopathy. (7) Refecting long clinical experience with MPL, the PLACE trial employed fixed
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laser parameters for treatment of all patients to maximize treatment safety; however, in a departure from precedents, the PLACE
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trial also elected to use twice the power of any prior study for low-duty cycled 810nm MPL. The reason for this decision is
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unclear, as the clinical effectiveness and safety of lower laser powers has been well established. While a goal of treatment in the
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PLACE trial is to avoid ophthalmoscopically visible laser lesions at the time of treatment, intra-treatment ophthalmoscopy may
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significantly underestimate actual LIRD. As doubling of the laser power increases the risk of retinal damage, it will be interesting
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to see how these treatment parameters fare in a large, although generally lightly pigmented, population. (7, 56)
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Branch Retinal Vein Occlusion
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Four studies have described the use of micropulse laser in the treatment of macular edema secondary to branch retinal vein
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occlusion (BRVO). Parodi and coworkers found no difference in results of subthreshold conventional-density grid laser treatment
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and RPC in terms of resolution of macular edema and improvement of visual acuity, although photocoagulation worked more
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quickly. (70)
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grid laser treatment in combination with intravitreal triamcinolone injection compared RPC for BRVO. (71) Luttrull, et al, included
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eyes with macular edema due to BRVO in a larger study demonstrating the danger of macular micropulse laser employing duty
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cycles above 5%. (56) More recently, Inagaki, et al, reported effective control of ME with subthreshold micropulse laser in
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patients with persistent macular edema due to BRVO and visual acuity better than 20/40. (30) Because macular edema due to
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BRVO tends to be a chronically waxing and waning condition, the ability to perform periodic retreatment safety with micropulsed
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lasers may be an aid to clinical management.
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Age related macular degeneration
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York, Glaser, and Murphy used indocyanine green angiography-guided micropulse laser to safely close choroidal feeder vessels
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in neovascular AMD. (97) In 2015, reversal of tolerance to anti-VEGF drugs in neovascular AMD was reported using SDM. (48)
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Thirteen eyes, unresponsive to all anti-VEGF medications for at least 6 months and 4 consecutive injections of aflibercept, were
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treated by MPL. One month later, anti-VEGF therapy was resumed. After re-challenge and resumption of aflibercept, macular
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exudation resolved in 12/13 eyes. They report that reversal of drug tolerance in wet AMD by MPL was predicted by “Reset to
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Default” theory, which postulates activation of RPE heat-shock proteins as the initiating mechanism of retinal laser treatment. As
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the first report of drug tolerance reversal in medicine, these findings lend strong support to the reset postulate. (48)
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In 2016, Luttrull and Margolis reported “functionally-guided panmacular micropulse laser” as “retinal protective therapy” (RPT) in high-risk dry AMD and inherited retinopathies. (50) Patients were evaluated before and after SDM RPT by pattern
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electroretinography (PERG) and visual function tests. After SDM RPT, 139/158 eyes were improved by PERG (P= 0.0001). VA
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was unchanged, but macular sensitivity by microperimetry (40 eyes) and mesoptic contrast visual acuity (73 eyes) improved (P =
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0.0439, and P = 0.006, respectively). Despite these improvements in retinal and visual function, no change in retina morphology,
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such as drusen number, size or distribution, was noted. Eyes with the worst preoperative measures improved the most following
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SDM by all indices (P = 0.0001). This included eyes with extensive geographic atrophy. By maintaining improved retinal function
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guided by early and periodic electrophysiologic signals, rather than late imaging signals, the authors hope to reduce the long-
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term risk of vision loss. (48, 50)
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In a subsequent retrospective study of 454 consecutive eyes of 296 patients in the Age-Related Eye Disease Study
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(AREDS) treated with panmacular SDM for high-risk dry AMD and followed a minimum of 1 year (range 1-7 years, avg 2 years),
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the incidence of new CNV was found to be less than 1% per year. (1) This was despite an average patient age of 83 years and
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high independent risk factors including fellow eye CNV (26%), reticular pseudodrusen (38%) and AMD severity (78% AREDS
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categories 3 and 4), all significantly exceeding the AREDS. These findings suggest that panmacular SDM may reduce the
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incidence of CNV in dry AMD more than vitamin therapy alone. In addition, in 409 of these same eyes, best-corrected logMAR
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mesopic visual acuity (p < 0.0001) and visual fields (P=0.0007) were also improved following panmacular SDM. There were no
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adverse treatment effects or LIRD. These findings suggest that retinal and visual function testing may be useful surrogate
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indicators of longer-term treatment benefits (or risks). (Figure 5) (Luttrull JK, Sinclair SH, Elmann S, Glaser BM. Panmacular subthreshold
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diode micropulse laser (SDM) for high-risk dry AMD: CNV Incidence and Mesopic visual function. Abstract and free paper presentation, American Society
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of Retina Specialists, annual meeting, Boston, August 8, 2017).
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Inherited retinopathies
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In addition to PERG in dry AMD, Luttrull and Margolis also reported SDM for a small group of inherited retinal degenerations
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(IRD). (50) PERGs were improved after SDM in 10 eyes of 8 patients with retinitis pigmentosa (RP, 4 eyes), cone degeneration
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(CD, 3 eyes) and Stargardt disease (Starg, 3 eyes) (p=0.002). While eyes with AMD improved most by a low-contrast PERG,
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IRD eyes improved most by the widest-field (240) high contrast PERG protocols. In both AMD and IRD, measures of signal
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latency improved most significantly. The authors note that both the functional improvements and the distinct PERG responses in
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AMD vs. IRD were predicted by the reset theory of retinal laser action. (50) More recently, updated results including 24 control
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and 34 treated eyes with non-age-related retinal degenerations (26 with RP, 3 CD, 4 Starg, and 1 with vitamin A deficiency)
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showed improved retinal function by PERG (27/34 eyes; P = 0.0003) and visual function by automated perimetry (20/21 eyes,
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P<0.0001) (Luttrull JK. Panmacular subthreshold diode micropulse laser (SDM) retinal protective therapy in non-age related retinopathies. Abstract
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and free paper American Society of Retina Specialists, annual meeting, San Francisco, CA, August 2016).
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Micropulse laser for neuroprotection in primary open angle glaucoma (POAG)
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Just as the reset theory of retinal laser action has successfully predicted reversal of anti-VEGF drug tolerance in AMD, and
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improved retinal and visual function in dry AMD and inherited retinal degenerations, reset theory also predicted that SDM should
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be neuroprotective. All chronic progressive retinopathies are examples of neurodegenerative disease. The purest case may be
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POAG, where there is no clinically discernable retinopathy. Recently, a retrospective study reported 88 consecutive eyes with
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advanced POAG marked by glaucomatous optic neuropathy and/or visual field loss evaluated before and after panmacular SDM
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by visually evoked potentials (VEP) and mesoptic automated perimetry. After treatment, significant improvements in both VEP
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P1 amplitudes (P=0.001) and mesopic visual fields (P<0.0001) were documented. There were no adverse treatment effects.
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SDM is thus the first treatment reported to improve visual fields absent pressure lowering in POAG; and the first treatment
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reported to improve the VEP and produce clinical neuroprotective effects. (53) (Figure 6)
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Navigated Micropulsed Laser
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Improved accuracy, eye tracking, computer based planning, enhanced training and documentation are advantages reported for
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navigated laser photocoagulation using the semi-automated NAVILAS® device. (2, 15, 36, 40) Recently, NAVILAS® became
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available with 577nm yellow laser with microsecond (micropulse) technology. (2) The NAVILAS® allows detailed documentation
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of sublethal micropulse laser application, with various duty cycle options along with navigated ability. Such documentation could
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be useful especially while repeating the subthreshold laser. Initial reports using this system showed success in CSR with
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juxta/subfoveal leaks. (Figure 7)
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PATTERN SCANNING LASERS
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Historically, retinal laser machines project a single laser beam through a coupled slit lamp biomicroscopic delivery system. Laser
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spots are applied to the retina under the direct observation of the operating surgeon. The laser beam is directed with a hand-held
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joy stick that manipulates the fiber optic or a reflecting mirror in order to point the laser spot to the precise retinal location desired,
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aided by a sub-therapeutic “aiming beam”, visible to the surgeon at all times. If many laser spot applications are required,
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treatment can be facilitated by an automatic “repeat mode”that fires the laser continuously with depression of the foot pedal until
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the pedal is released. (41)
In 2005, Optimedica introduced the first partially automated retinal laser system, called the “pattern scanning laser”, or
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“PASCAL”. (5) The PASCAL allowed the operator to select from several small preset patterns of various shapes, and apply
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photocoagulation to the retina in these patterns with a single depression of the foot pedal. To cover larger treatment areas, these
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preset patterns are then serially redirected to different retina locations with a joystick, in the same way that manual lasers redirect
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single spots.
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In order to deliver preset 5 x 5 grids of 25 single sequentially placed shots of retinal photocoagulation safely (prior to
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patient movement or blinking), a high scanning speed, and thus low laser pulse duration, is required. The developers of the
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PASCAL theorized that the driving force for progression of DR was retinal oxidative stress caused by retinal photoreceptor
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oxygen consumption. According to this theory, effective treatment of DR required selective destruction of at least 30% of retinal
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photoreceptors. Thus, a short-pulse (10-20ms) duration CW 532nm laser was employed that could selectively destroy the outer
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retina within the time constraints of pattern application limited by patient fixation. (32, 33, 46)The pattern scanning laser has been
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reported to be comparably effective to conventional photocoagulation, but with less retinal damage, in the treatment of diabetic
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macular edema. (33)
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Because of the short pulse duration and limited heat-spread from the center of the photocoagulation spot, PASCAL PRP may be more comfortable for patients than conventional PRP. Possibly reflecting the dynamics of selective retinal ablation as
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described above, PASCAL photocoagulation has been reported to be less effective than conventional photocoagulation. (3, 13,
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29, 33, 64, 65) Increasing the treatment density of PASCAL treatment by 2- 3x, or more, compared to conventional
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photocoagulation, has been recommended to improve clinical results. (13) Reflecting the biophysics of SRA (discussed above),
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however, a recent report from the Diabetes Clinical Research Network found that, despite increased treatment density, the
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pattern scanning laser was less effective than ranibizumab or conventional panretinal photocoagulation for proliferative diabetic
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retinopathy. (3, 29)
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platforms designed for photocoagulation have been repurposed to perform sublethal treatment. This includes the pattern-
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scanning laser. (45) Confirming the ANSI MPE predicted narrow TR of 0.010 watts for CW lasers with in vivo animal studies of
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HSP activation, an algorithm called “end point management” (EPM) was created to aid PASCAL users attempting to avoid LIRD.
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(45, 46, 47, 88) With EPM, the surgeon determines the laser power to create a “barely visible” retinal burn at the margins of the
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selected grid pattern. If the surgeon has judged the test burn correctly, and the power is then decreased by 70%, the algorithm
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predicts that treatment should fall within the 0.010 watt-wide therapeutic window. (45, 46, 47, 88)
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To date, a single report of clinical EPM application has been published, in a small series of eyes with CSR. (45) No laserinduced retinal damage was noted; however, treatment results were modest; with a low rate of single treatment success, a high
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rate of recurrence and repeat treatment, and a high rate of treatment failure. (45) Because of the narrow TR of short-pulse CW
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laser, the risk of ineffective treatment is as high as inadvertent retinal burns. (45, 46, 47, 88)
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Although it has been suggested that PASCAL EPM can be used safely in the fovea, this remains to be demonstrated. (45) The EPM algorithm was developed in animal models with homogenous RPE melanin distribution. Human RPE melanin
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distribution, by contrast, is heterogeneous. (45, 46, 88) This heterogeneity may lead to variable laser uptake in patients at
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different retinal foci, as long experience with conventional photocoagulation attests. Reliance on subjective assessment of retinal
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test burns is inherently problematic. As LIRD may be invisible to the surgeon at the time of treatment, there is a real potential for
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visual loss due to inadvertent foveal injury if subjective assessment of laser intensity is in error. (54) Successfully hitting the
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narrow CW TR target to allow reliably safe CW treatment of the human fovea will likely require technology not yet available, such
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as accurate real-time RPE reflectometry.
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Most current commercial retinal laser manufactures now offer semi-automatic pattern scanning capabilities modeled on
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the PASCAL. While the PASCAL adheres to its original short-pulse CW format, other pattern scanning platforms offer
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conventional photocoagulation and / or micropulsed laser modes, including the NAVILAS, which has the capacity to be fully
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automatic. (15) While pattern scanning is aesthetically pleasing, the therapeutic benefit of various treatment patterns has not
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been established.
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Finally, several pattern scanning laser platforms also offer treatment mapping of the treatment location and document treatment parameters. This is designed to aid the surgeon considering re-treatment. Because retinal photocoagulation produces
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retinal damage easily seen by clinical exam or imaging postoperatively, the location of prior treatment is not generally in doubt.
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By the same token, local targeting is not a strategy of sublethal micropulse retinal laser treatment, which is currently applied in a
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“panmacular” fashion. (48, 50) Sublethal treatment can, by definition, be repeated as necessary without regard for the location of
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prior treatment. Thus, the clinical value of treatment mapping for retinal restorative treatment sublethal to the retina is unclear.
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certain costs. These include the cost of the technology itself, as well as the additional time required to select and program the
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desired mode of treatment for each patient. Particularly for performance of treatment sublethal to the retina, it is unclear whether
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these technologies offer actual advantages in treatment effectiveness and efficiency over an active joystick and foot on the
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repeat-mode pedal; however, in the search for further improvements in treatment efficacy, safety, and efficiency, further
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automation and improvements in retinal laser technology is a certainty.
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SELECTIVE RETINA THERAPY (SRT)
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The efficacy of conventional laser treatment for the treatment of DME was demonstrated by the ETDRS randomized clinical trial
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and the modified ETDRS study; (72) however, conventional laser treatment is associated with the destruction of full thickness
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retinal tissue and causes several side effects such as central scotomata, retinal hemorrhages, and choroidal neovascularization.
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Lesser power laser treatment for the macula was applied to avoid these complications of conventional laser in the modified
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ETDRS study. To further reduce retinal tissue damage, selective retina therapy (SRT) using microsecond pulses has been
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developed to obtain selective RPE damage while sparing adjacent photoreceptors or the choroid.
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Theory of SRT
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For the various retinal diseases associated with the dysfunction of the RPE, such as age-related macular degeneration (AMD),
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CSR, and DME, it might be sufficient to damage the RPE selectively without damaging the adjacent photoreceptors, the neural
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retina, and the choroid. The healing response to SRT has been called “retinal rejuvenation”. Just as with the PASCAL and nano-
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second (other short-pulse CW) lasers, it accomplished by cells adjacent to the LIRD expanding and sliding in to fill the laser
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defect. In mice proliferation RPE has been reported as part of the wound repair. This has not been observed in humans. (70)
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Although the precise mechanism of SRT is not fully understood, two theories can be considered to partially explain the unknown
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mechanism. One theory suggests that the beneficial effects of SRT are associated with the establishment of a new RPE cell
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barrier, with subsequent restoration of the RPE pump and barrier integrity. The other theory is that the bioactive substances such
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as matrix metalloproteinases (MMPs) and HSP 70 might play a role for therapeutic effect of SRT during healing process of RPE.,
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(9, 22, 72, 87, 89) Such theoretical considerations and the limitation of conventional laser treatment have led to the development
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of SRT laser treatments that selectively affect the RPE.
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The basis for selective RPE damage can be found in the light absorbing melanosomes within RPE cells that are influenced by
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certain wavelengths. About 50 % of laser with a green spectral range is absorbed in the RPE layer, and pulse energy is
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absorbed primarily by melanosomes within RPE cells. (47) In addition to wavelength, exposure time of pulse laser is an
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important parameter because the spatial extent of elevated temperature is reduced when multiple laser pulses of short duration
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are delivered. Thus, for achieving RPE selectivity, the effect of laser can be confined to the RPE cells by manipulating the pulse
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duration. The exposure time of each pulse is set in the microsecond range rather than of millisecond to prevent heat spread
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beyond the RPE, (~10um) sparing adjacent tissue structures. (10, 46) If the pulse energy is adequate, shorter than 5
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microseconds RPE cells are damaged by microvaporization around intracellular melanosomes. High peak temperatures that
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develop around melanosomes during micropulse laser irradiation create short-lived microbubbles that markedly increase the cell
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volume, leading to a mechanical disruption of RPE cells. (66) The SRT technique avoids the formation of macrobubbles that is
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associated with a risk of photodisruption of the retina or choroid. (23, 66, 76) Overall, SRT stimulates RPE cell expansion /
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migration into irradiated areas to improve metabolism at diseased sites without directly damaging adjacent retinal layers.
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Treatment endpoints of SRT
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Since SRT lesion is invisible on funduscopy, fundus fluorescein angiography (FFA) is the most reliable method to detect SRT
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lesions currently. Although SRT lesions showed transiently increased autofluorescence several days after SRT treatment, no
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instant change of SRT spot was observed on fundus autofluorecence in the previous studies. (78, 80, 81) Therefore, to confirm
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selective RPE damage quickly, two treatment endpoints including invisibility on fundoscopy and visibility on fluorescein
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angiography are used clinically. Two studies have demonstrated that FFA-positive SRT spots were faintly visible 1 week after
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SRT treatment and disappeared by 3 months. (20, 95) These clinical findings are consistent with the result of an in vivo animal
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experiment that SRT-treated defects were covered by intact bystander RPE cells within 7 days. (72, 73) The first SRT clinical trial
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using an Nd:YLF laser system and a pulse duration of 1.7 microseconds (100 pulses, at 100 and 500 Hz) revealed the potential
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effect of SRT in clinical use. (9) Subsequently, the SRT laser parameters were refined with even shorter pulses and fewer
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repetition rates. (23) Currently, SRT Laser system (R:GEN, Lutronic, Goyang-si, South Korea), Q-switched Nd:YLF laser: wave
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length; 527nm, micropulse duration; 1.7 µs, repetition rate; 100Hz, maximum number of micropulses in a burst:15) is used
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clinically. However, to find out the adequate therapeutic range of SRT treatment for individual patient, fluorescein angiography for
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test spots is mandatory before treatment spot irradiation.
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Real-time feedback-controlled dosimetry (RFD) during irradiation
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As with subthreshold micropulse laser (SDM), SRT does not cause visible changes in the retina, making it difficult to determine
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the adequate pulse energy of the laser. Even though pretreatment fluorescein angiography is useful method to detect RPE
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damages, it could be difficult for physician to monitor adequate RPE damage due to the wide range of inter or intrapersonal
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variation of retinal pigmentation. Therefore, to titrate the pulse energy in real-time without fluorescein angiography, optoacoustic
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(OA) and reflectometric (RM) methods for SRT have been developed. As transient microbubbles during SRT irradiation are
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responsible for the desired effects on RPE cells, it is useful to monitor microbubble development. (66) For detecting the
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appearance of microbubbles in real-time, OA and RM method detect feedback signals originating from microbubbles. Briefly, OA
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device detects the ultrasonic pressure as a form of optoacoustic feedback value (OAV) from microbubbles. (79, 80) RM device
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detects inflection of backscattered light as a form of optical feedback value (RV) from microbubbles. After each burst, based on
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the amplitude of feedback signals of each dosimetry, algorithm of dosimetry was optimized to obtain adequate RPE damages
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and to avoid both undertreatment (low OAV and RV due to no or tiny microbubbles) and overtreatment (high OAV and RV due to
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macrobubbles associated with burns). After evaluating the correlation between angiographic findings of SRT spots and the
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feedback signal form SRT spots, the sensitivity and specificity of OA dosimetry were 86% and 70% respectively and the
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sensitivity and specificity of RM dosimetry were 89% and 94% respectively. (79, 80) Although the accuracy of each dosimetry is
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already clinically applicable, the accuracy of dosimetry is expected to be improved by adopting two dosimetries simultaneously.
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Therefore, the real-time feedback-controlled dosimetry (RFD) implemented with both OA and RM method was developed.
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One of the major obstacles in SRT treatment is the risk of undertreatment when adequate pulse energy is chosen according to
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the angiographic finding from test spots, since there is a discrepancy in tissue structure of healthy test area and diseased
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treatment area. SRT with real-time feedback-controlled dosimetry algorithm (RFD-v1.0) using OA and RM devices provides OA
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feedback value and RAV value concurrently. One SRT spot consists of maximum of 15 micropulses (increment of 3.57% for the
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following micropulse). The first micropulse is set to be 50% of the last 15th micropulse. (Figure 8) When SRT irradiation reached
490
the therapeutic threshold at which microbubbles occur in the RPE, adequately damaging the cells, the following micropulse is
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stopped automatically by RFD-v1.0. According to the algorithm that is designed to obtain the margin of safety, RFD gives three
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kinds of alarm signal based on the placement of automatic stop; automatic stops before 4th micropulse among 15 micropulses
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indicate an alarm for overtreatment, automatic stops after 12th micropulse indicate an alarm for undertreatment. Therefore, the
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physician can adjust the pulse energy based on these signals instantly to maintain the adequate pulse energy (automatic stops
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between 4th and 12th micropulse). (76)
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Clinical studies
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Diabetic macular edema
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Roider et al. reported that 33/39 eyes (84 %) with DME showed stable or improved visual acuity over a 6 month follow-up by
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using SRT treatment with OA method (81) (Similarly, in another uncontrolled prospective study, 16/23 eyes (70.%) of patients
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with DME showed improvement of more than one ETDRS line, and improvement of 1.7 dB in mean macular sensitivity was
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observed 6 months after SRT treatment with microperimetry. (69) In addition, retreatment with SRT also positively influenced a
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reduction of macular thickness 6 months after SRT. These clinical studies support for the safety and efficacy of SRT.
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Furthermore, the disappearance of SRT spot on FA at 3 months and the fading of transiently increased autofluorescence of SRT
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spot after SRT indicate the restoration of RPE monolayer. (69) Despite the differences of dosimetry and the baseline
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characteristics of the patients between two studies, SRT showed favorable results in these two prospective studies. The
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treatment strategy of SRT was to cover the edematous lesion with one-spot space between SRT spots rather than no-space to
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allow adjacent RPE cells for RPE healing. However, larger randomized clinical trials are needed to confirm the optimized density
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of spots and the efficacy of SRT treatment.
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Central Serous Chorioretinopathy
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Since dysfunction of RPE is one of important cause for development of subretinal fluid (SRF) in patients with CSR, SRT can be
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helpful to promote resolution of SRF by RPE rejuvenation. Klatt et al. reported that 71.4 % of 14 patients in SRT group showed a
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complete resolution of SRF compared to 40% of 16 patients of control group. (38) SRT was applied to cover all leaking points on
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fluorescein angiography for 12 eyes of 12 patients with chronic CSR 3 months after SRT. In this study, mean BCVA (logMAR)
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improved from 0.23 ± 0.12 at baseline to 0.14 ± 0.13 at 3 months. SRF completely resolved in 75% (9 eyes) at 3 months.
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Moreover, no scotomata were observed in the SRT-treated regions by microperimetry. However, under-treatment due to SRF
517
was suspected in some of treatment spots because of the decreased amplitude of feedback signals in this study. To decrease
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the risk of under-treatment, when the RFD provides an alarm signal based on the placement of automatic stop (from 12th and
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15th micropulse) the pulse energy can be increased by the operating surgeon instantly. (38) More recently, Yasui et al reported
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resolution of macular fluid present 3 months or more in 11/17 eyes with CSR. Visual acuity and microperimetry were improved,
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without treatment-associated scotomata. (95) (Figure 9)
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Drusen in Age Related Macular Degeneration
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As mentioned above, drusen reduction could be one of potential indication for SRT, in that LIRD is known to increase the release
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of activated MMPs. (22, 98) Roider et al. reported that 3 of 10 patients with drusen showed disappearance of drusen 3 months
525
after SRT. (77) In another study, SRT was performed for soft drusen in two eyes. One eye did not change. In the other, there
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was some resolution of the drusen after 6 months (78) Conventional laser therapy for drusen is believed to have failed because,
527
although LIRD promoted disappearance of drusen, it also increased the risk of choroidal neovascularization. (90) This is may be
528
due to LIRD to Bruch membrane. Histologically, SRT has not produced breaks in Bruch membrane in previous studies; however,
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a study of SRT for age-related geographic atrophy (GA) in 6 eyes found that SRT accelerated the rate of GA progression by 50%
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compared to fellow eye controls. (77) This worsening was attributed to the LIRD produced by SRT, further emphasizing the risks
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of LIRD in dry AMD.
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Currently, SRT treatment requires fluorescein angiography for titration of pulse energy. Any discrepancy between the feedback signals from the test treatment areas require instant adjustment of the laser parameters to avoid under – or over-
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treatment, especially in the macula. SRT with RFD could assist titration of the pulse energy, by reducing reliance on subjective
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observations of laser-induced retinal opacification. A clinical trial is planned to validate the safety and efficacy of SRT with RFD in
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the near future.
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Effects of nanosecond laser treatment in animal models of disease
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Over the last 20 years research has focused on improving the selectivity of laser treatment to the RPE so as to reduce the level
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of collateral damage to the overlying retina that resulted from traditional continuous wave pulse lasers. (10, 23, 32, 49, 51, 59, 77,
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93) Pulsed lasers in the nanosecond range deliver a fraction of the energy of traditional continuous wave lasers, and provide a
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means for selectively targeting the RPE, whilst reducing damage to neighboring structures. (32) The selective effect of
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nanosecond laser treatment on the RPE has been investigated in rodent and human retinas. (17, 34, 94) Notably, a single 3
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nanosecond laser pulse of 0.065mJ induced a lesion predominantly within the RPE that healed within 7 days. (34) During the
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healing phase RPE cells immediately adjacent the laser-ablated area enlarge to re-epithelialize the lesion. In addition,
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proliferation of cultured human RPE cells has been demonstrated following nanosecond laser treatment with mouse RPE cells
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neighboring laser-ablated lesions immunoreactive for the cell cycle marker, cyclin D1. (17)
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The integrity of the retina overlying laser lesions induced by either a continuous wave laser suprathreshold or clinically-
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relevant nanosecond laser energy level has been investigated in rat, mouse and human retina. In contrast to treatment with a
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CW laser of the same wavelength (532nm), a nanosecond laser pulse set at a clinically appropriate laser energy (0.065mJ) was
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not associated with cell death in overlying photoreceptors in the mouse, nor disruption of Bruch membrane within the lasered
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region of a rat (energy setting 0.21mJ). (17, 34) These results have been confirmed in human retinae by immunocytochemical
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analysis or SD-OCT imaging 5 days following laser treatment (90). In contrast, higher nanosecond laser energies were
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associated with cell death of overlying photoreceptors, Müller cell gliosis, and an inflammatory reaction in rodent retina (17, 34,
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94). Retinal integrity was maintained after multiple treatments at the same anatomical site. These results highlight that treatment
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with a nanosecond laser pulse set at a clinically appropriate energy setting induces selective loss of the RPE without major
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effects on the overlying retinal neurons.
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The mechanism by which nanosecond laser treatment induces selective RPE cell loss is not well understood. It is well
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established that CW laser energy is absorbed by melanosomes within the RPE, causing thermal damage that diffuses into
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adjacent tissues. The Arrhenius law that describes the relationship between tissue temperature and damage is thought to hold
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for laser pulses down to the millisecond range; (16, 56) however, when laser pulses are of shorter duration the cellular effects
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can no longer be attributed to thermal damage, but rather may involve thermomechanical effects. (80) It is currently thought that,
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following exposure to a nanosecond laser pulse, approximately 50% of the laser energy is absorbed by melanin granules,
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causing a localized temperature rise around the melanin. Cell death occurs because of the formation of microbubbles that form
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around melanin granules that leads to cell expansion and rupture. (79)
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The major clinically relevant effects induced following nanosecond laser treatment include resolution of drusen in patients
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with intermediated age related macular degeneration and thinning of Bruch membrane in aged mice. (27, 34) Using ApoEnull
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mice, a mouse strain known to develop a thickened Bruch membrane, Jobling et al showed reduction in Bruch membrane
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thickness three months after treatment with nanosecond laser. (93) In addition, a range of changes in gene expression within the
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RPE were documented. In particular, nanosecond laser treatment was associated with a change in mRNA expression of a range
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of extracellular matrix genes that were consistent with the changes in Bruch membrane observed. Notably, expression of matrix
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metalloproteinases 2 and 3 as well as tissue inhibitors of matrix metalloproteinases (TIMP) were dysregulated in the RPE of
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lasered ApoEnull mice compared to unlasered age matched controls. Similarly, nanosecond laser treatment of cultured human
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RPE induced release of MMP2 and MMP9. (93)
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One of the more intriguing findings observed following treatment with a nanosecond laser are effects on the non-lasered
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fellow eye. In a subset of patients, nanosecond laser treatment was associated with a reduction in drusen in the fellow non-
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lasered eye. (27) In mice, similar changes in extracellular matrix gene expression occurred in both the lasered and non-lasered
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fellow eye. Although the mechanism(s) by which the fellow non-lasered eyes are influenced by nanosecond laser remain unclear,
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it is possible that early immune cell changes that occur within the first hour following treatment may play a role. (11) Indeed,
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activated microglia have been shown previously to alter RPE gene expression and function. Further work is needed to further
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explore the mechanisms underlying the effects of laser on the fellow eye, and its implications for clinical care of patients.
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In summary, the recent development of nanosecond lasers offers a means of selectively ablating the RPE, whilst sparing
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adjacent tissues. Recent animal studies suggest that treatment with a nanosecond laser induces a healing effect within the RPE
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that is associated with broad changes in the expression of extracellular matrix genes as well as thinning of Bruch’s membrane.
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Clinical studies
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The safety and efficacy of short-pulse, nanosecond (retinal rejuvenation therapy, 2RTTM) laser (Ellex Pty Ltd, Adelaide, Australia)
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has been investigated in the treatment of DME and AMD (12, 27, 34, 73, 93) The 2RTTM laser is a 532 nm Q-switched YAG
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laser. In these pilot studies, laser spots of 400 µm are delivered at short pulses of 3 nanoseconds to the macula, outside the
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fovea. Subthreshold treatment energy for each individual is typically determined to be the energy level, one step lower than
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visible retinal blanching, observed in a test spot placed outside the macular region.
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Diabetic Macular Edema
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To examine if nanosecond laser treatment was non-inferior to conventional laser treatment in DME, Casson et al.
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conducted a 6-month pilot trial involving 38 eyes. (12) Nanosecond laser treatment involved application of the laser spots in a
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grid pattern to the thickened macular regions, with no direct treatment to microaneurysms. The treatment spots were 400µm
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apart, and at least 500 µm from the fovea center, resulting in approximately 20 to 120 applications per eye. Conventional thermal
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photocoagulation treatment involved targeting leaking microaneurysms with light burns of spot size of 100 um and duration of
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0.1s, and using the ETDRS direct/grid on only areas of thickened retina. Nanosecond laser and conventional laser resulted in
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similar change in central macular thickness (CMT) and VA 6 months post-treatment. In this study, treatment randomization was
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performed without blocking or stratification, resulting in a disproportionate gender representation in treatment groups. The
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treatment energy for the nanosecond laser was reported to be approximately 0.3 mJ; however, it is unclear the total energy that
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was used for treatment, including cases that was re-treated.
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Pelosini et al further investigated the efficacy of nanosecond laser treatment in 28 eyes with DME. (73) Nanosecond laser
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treatment was administered in a similar fashion to Casson and coworkers,, with areas of edema indicated by angiographic
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images. The treatment energy level was set at 0.3 mJ. Visible retinal blanching observed with 0.6 mJ and variable degrees of
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retinal reaction with 0.5 mJ. (12) The number of treatment shots ranged from 14 to 232. Re-treatment at 0.3 mJ was performed in
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14 eyes (50%) 4 months after initial laser. The loss of 10/28 eyes (36%) to follow up by 6 months resulted in different outcomes 3
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month versus 6 month post-initial laser and makes interpretation of the study results problematic. While improvement in VA was
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not significant at 3 months, VA was significantly improved at 6 months. CMT was significantly reduced from baseline for the 3-
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month cohort, but not for participants followed for 6 months. A moderate improvement in fixation stability and microperimetric
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retinal sensitivities was observed at 3 months. Subanalysis did not reveal differences due to gender. The absence of functional
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loss as indicated by retinal sensitivity assessment and visual acuity suggested that photoreceptor damage was absent or
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minimal. In addition, the efficacy of nanosecond laser treatment was supported by the reduction or stability of CMT and
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angiographic leakage at 6 months. A randomized controlled trial and a longer follow up period will provide further evidence of
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nanosecond laser as a safe and effective treatment for DME.
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Age Related Macular Degeneration
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Guymer et al applied 12 spots of 2RTTM nanosecond laser around the macula of one eye in 50 people with bilateral
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intermediate AMD with the aim of slowing the progression of the disease. (27) Treatment locations were initially 1500 um from
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the fovea center in a ring; however, after investigators noted a widespread effect on the clinical macular appearance, the protocol
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was revised to require the treatment spots to be moved out to be just inside the superior and inferior arcades in an arc following
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the arcades. Treatment energy was set 20% lower than visible test spot energy. Following the use of 0.45 mJ in a test shot with
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a resultant dot hemorrhage in one eeye, the maximum energy was set at 0.3 mJ for subsequent treatments. Treatment energy
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ranged from 0.15 mJ to 0.45 mJ, with an average of 0.24 mJ. Nanosecond laser treatment did not improve VA in the treated eye
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at 12 months, while improvement in visual function was found in the worst point flicker sensitivity 1º from the fovea center of the
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treated eye at 12 months. Nanosecond laser treatment resulted in reduction (> 5% less from baseline) of drusen area in 44% of
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treated eyes at 12 months. Comparison with an historical control group (n= 116 eyes) revealed that this proportion was
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significantly greater than that observed in natural history. Drusen regression with one application of nanosecond laser treatment
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was maintained at 24 months, with 35% of treated eyes demonstrating this characteristic as compared to 11% in the natural
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history cohort. Of great interest, drusen regression was also observed in 22% of the fellow untreated eyes in the nanosecond
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laser-treated group at 12 months. Fundus autofluorescence (FAF) assessment of areas of drusen regression in a subgroup of
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nanosecond laser treated eyes at 12 and 24 months post-laser demonstrated stable FAF when compared to baseline in 9 of 12
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eyes. This allayed concerns of drusen regression from treatment leading to geographic atrophy (GA), as had been reported to be
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a natural sequel to drusen resolution in AMD. (96) Improvement in flicker threshold within the central 3° was observed in both the
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treated and untreated fellow eyes at 3 months post-laser. Of the 11 eyes presumed to be at greatest risk of progression (flicker
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defect > 15 dB), seven improved sufficiently to be taken out of this high-risk category. (Figure 10) The short follow up period in
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this study did not reveal if nanosecond laser treatment was effective in decreasing the number of cases that progressed to late
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AMD. The authors however cautioned against nanosecond laser treatment in patients with large (> 1000 µm) subfoveal
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drusenoid pigment epithelial detachments, as two participants with this feature lost vision over the follow up period from GA. The
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results of this study provided enough evidence to pursue nanosecond laser as a potential therapeutic intervention for AMD and a
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randomized controlled trial is currently being conducted to investigate if nanosecond laser can slow disease progression in
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intermediate AMD within 36 months (The LEAD study, clinicaltrials.gov: NCT01790802).
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CONCLUSION
The promise of laser retinal restoration therapy appears real and potentially important. Clinical observations and
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laboratory studies arising from the effectiveness of retina-sparing laser treatments have improved our understanding of the
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mechanism(s) of retinal laser therapy, replacing old concepts presuming the need for laser-induced retinal destruction, with
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laser-induced restoration of retinal and visual function. Recent reports of treatment applications beyond the conventional
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indications of DR and CSR may significantly expand future applications for retinal laser therapy. What remains is validation by
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larger, randomized trials. The weight and consistency of clinical and experimental data, and the convergence of thought we
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report, should increase the momentum for such studies.
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Method of Literature Search
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A systematic literature search of the Medline/PubMed database (www.ncbi.nlm.nih.gov/pubmed) was performed in December
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2016, using the following search parameters: Laser photocoagulation; subthreshold laser; micropulse laser; retinal laser;
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microsecond laser; panretinal photocoagulation; PASCAL; NAVILAS; Pattern Scanning Lasers; nanosecond laser; selective
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retina therapy; endpoint management; 2RT. Both English and non-English literature was included. The reference lists of the
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identified publications provided additional information and related sources. In keeping with the focus of this work, papers
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representing recent developmental milestones especially relevant to restorative retinal laser treatment, or new technological
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advances toward this end, were preferred for inclusion.
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The authors have no financial conflicts.
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Disclosures:
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44 JKL: Ojai Retinal Technologies, LLC, Ojai, California: Management, equity, patent.
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Retinal Protection Sciences, LLC, Ojai, California: Management, equity, patent.
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Ocular Proteomics, LLC, Towson, Maryland: Consultant
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Replenish, Inc, Pasadena, California: Equity, patent.
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78 Roider J, Brinkmann R, Wirbelauer C, et al: Variability of RPE reaction in two cases after selective RPE laser effects in prophylactic treatment of drusen. Graefes Arch Clin Exp Ophthalmol 237:45-50, 1999 79 Roider J, El Hifnawi ES, Birngruber R: Bubble formation as primary interaction mechanism in retinal laser exposure with 200-ns laser pulses. Lasers Surg Med 22:240-248, 1998 80 Roider J, Hillenkamp F, Flotte T, Birngruber R: Microphotocoagulation: selective effects of repetitive short laser pulses. Proc Natl Acad Sci U S A 90:8643-8647, 1993 81 Roider J, Liew SH, Klatt C, et al.: Selective retina therapy (SRT) for clinically significant diabetic macular edema. Graefes Arch Clin Exp Ophthalmol 248:1263-1272, 2010
ACCEPTED MANUSCRIPT 51 82 Schatz H, Madeira D, McDonald HR, Johnson RN: Progressive enlargement of laser scars following grid laser photocoagulation for diffuse diabetic macular edema. Arch Ophthalmol 109:15491551, 1991
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83 Shimoda K. Introduction to Laser Physics, 2nd Ed. Iwanami Shoten Pub., Tokyo 1983. IBSN 978-3540-16713-6. 84 Sivaprasad S, Elagouz M, McHugh D, et al.: Micropulsed diode laser therapy: evolution and clinical applications. Surv Ophthalmol 55:516-530, 2010
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85 Sivaprasad S, Sandhu R, Tandon A, et al.: Subthreshold micropulse diode laser photocoagulation for clinically significant diabetic macular oedema: a three-year follow up. Clin Exp Ophthalmol 35:640644, 2007
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86 Sliney DH, Mellerio J, Gabel VP, Schulmeister K: What is the meaning of threshold in laser injury experiments? Implications for human exposure limits. Health Phys 82:335-347, 2002 87 Sramek C, Mackanos M, Spitler R, et al.: Non-damaging retinal phototherapy: dynamic range of heat shock protein expression. Invest Ophthalmol Vis Sci 52:1780-1787, 2011 88 Sramek CK, Leung LS, Paulus YM, Palanker DV: Therapeutic window of retinal photocoagulation with green (532-nm) and yellow (577-nm) lasers. Ophthalmic Surg Lasers Imaging 43:341-347, 2012
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89 Treumer F, Klettner A, Baltz J, et al.: Vectoral release of matrix metalloproteinases (MMPs) from porcine RPE-choroid explants following selective retina therapy (SRT): towards slowing the macular ageing process. Exp Eye Res 97:63-72, 2012 90 Varley MP, Frank E, Purnell EW: Subretinal neovascularization after focal argon laser for diabetic macular edema. Ophthalmology 95:567-573, 1988
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91 Vujosevic S, Bottega E, Casciano M, et al.: Microperimetry and fundus autofluorescence in diabetic macular edema: subthreshold micropulse diode laser versus modified early treatment diabetic retinopathy study laser photocoagulation. Retina 30:908-916, 2010
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92 Vujosevic S, Martini F, Longhin E, et al.: SUBTHRESHOLD MICROPULSE YELLOW LASER VERSUS SUBTHRESHOLD MICROPULSE INFRARED LASER IN CENTER-INVOLVING DIABETIC MACULAR EDEMA: Morphologic and Functional Safety. Retina 35:1594-1603, 2015 93 Wood JP, Plunkett M, Previn V, et al.: Nanosecond pulse lasers for retinal applications. Lasers Surg Med 43:499-510, 2011 94 Wood JP, Shibeeb O, Plunkett M, et al.: Retinal damage profiles and neuronal effects of laser treatment: comparison of a conventional photocoagulator and a novel 3-nanosecond pulse laser. Invest Ophthalmol Vis Sci 54:2305-2318, 2013
ACCEPTED MANUSCRIPT 52 95 Yasui A, Yamamoto M, Hirayama K, Shiraki K, Theisen-Kunde D, Brinkmann R,Miura Y, Kohno T. Retinal sensitivity after selective retina therapy (SRT) on patients with central serous chorioretinopathy. Graefes Arch Clin Exp Ophthalmol.2017 Feb;255 (2):243-254.s
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96. Yehoshua Z1, Wang F, Rosenfeld PJ, et al. Natural history of drusen morphology in agerelated macular degeneration using spectral domain optical coherence tomography. Ophthalmology. 2011 Dec; 118 (12):2434-41. 97 York J, Glaser B, Murphy R. High speed ICG. Used to pinpoint laser treatment of feeder vessels in wet AMD. J Ophthalmic Nurs Technol. 19(2):66-67.
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Figure legends
Figure 1: Optical coherence tomography before (top); 3 months after (middle); and 6 months after (bottom) panmacular SDM laser for center-involving diabetic macular
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edema. Note reduction in macular thickening and resolution of macular exudates without laser-induced retinal damage. Snellen visual acuity 20/40 prior to treatment; and
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20/25 after treatment.
Figure 2: Late-phase intravenous fundus fluorescein angiographs of eye with severe non-proliferative diabetic retinopathy before (left) and 9 months after (right) a single treatment session of panmacular and panretinal SDM laser. Note regression of retinopathy, decrease micro-and macro vascular leakage, and capillary re-perfusion
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without laser-induced retinal damage. (Note: photographic timer is in error. Actual postinjection time for each photograph is approximately 10 minutes).
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Figure 3: Late-phase intravenous fundus fluorescein angiographs of eye with proliferative diabetic retinopathy before (left) and 5 months after (right) a single
treatment session of panretinal SDM laser. Note regression of neovascularization with decreased leakage of dye; reversal of background retinopathy severity; and absence of
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laser-induced retinal damage. (Note: Photographic timer is in error. Actual post-injection
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time for each photograph is approximately 10 minutes).
Figure 4: 10-minute post-injection intravenous fundus fluorescein angiographs of eye with proliferative diabetic retinopathy before (left) and 3 years after (right) a single treatment session of panretinal SDM laser. Note regression of neovascularization
severity.
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inferiorly, with decreased leakage of dye and reversal of background retinopathy
Figure 5: Omnifield threshold resolution (mesopic) perimetry visual field tests of the right
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eye of a patient with dry age-related macular degeneration, AREDS (Age Related Eye Disease Study) Category 3. The Omnifield measures the thresholds for best-corrected
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logMAR visual acuity under mesopic conditions at various intercepts throughout the central 200 of the visual field. A computer algorithm then uses these measurements to construct a false-color map (perimetry) of mesopic visual acuity thresholds through out the tested area. (A) Omnifield of right eye before; and (B) 3 months after SDM. Note improvements in all indices after SDM. BA6 = Best logMAR visual acuity (VA) within 60 of fixation; GMA = global macular acuity, or average logMAR VA in the central 200.
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Figure 6: Omnifield threshold resolution (mesopic) perimetry visual field tests of patient with advanced primary open angle glaucoma, before (left) and after (right) panmacular SDM laser. Note marked improvements after SDM laser. BA6 = Best logMAR visual
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acuity (VA) within 60 of fixation; GMA = global macular acuity, or average logMAR VA in central 200; VA=visual angle.
Figure 7: A 27-year old male with central serous chorioretinopathy showing retinal
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epithelium changes on color photograph (A) with juxtafoveal leak on fluorescein
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angiography (B and C). Spectral domain optical coherence tomography shows presence of subretinal fluid at baseline (D). Complete disappearance of subretinal fluid was noted after single session of navigated microsecond laser (E) at one month. Figure 8. The laser pulse energy is irradiated in a ramping manner (increment of 3.57%
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for the following micropulse) for every selective retina therapy (SRT) spot. Based on the algorithm of real-time feedback-controlled dosimetry (RFD-v1.0), if RFD detects the feedback signals from microbubbles at 7th micropulse, 8th micropulse wouldn’t be
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irradiated automatically.
Figure 9: A 45-year-old man presented with a 4-month history of subretinal fluid (SRF)
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in his right eye and diagnosed as central serous chorioretinopathy. Best-corrected visual acuity of right eye was 20/40. A. SRF on macular optical coherence tomography (OCT) was observed at initial presentation. B. SRF was completely resolved 1 month after receiving selective retina therapy (SRT) with real-time feedback-controlled dosimetry (RFD). C. Fluorescein angiography (FA) showed multiple focal leaking points at macular region. D. Initial fundus autofluorescence. E. There was no change on
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autofluorescence 1hr after SRT. F. Hyperfluorescence of SRT test spots (yellow box) was observed 3 hours after SRT. After ten SRT treatment spots (yellow arrowhead)
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were applied, multiple fluorescein leakages were also detected on FA. Figure 10: Color fundus images (A and B) and retinal pigment epithelium (RPE) layer maps from spectral domain optical coherence tomography (OCT) (cirrus) (C and D) of a
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Table 1: Studies on use of subthreshold micropulse laser in Diabetic macular edema
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Results Compared conventional argon to micropulsed diode photocoagulation - VA remained stable in both groups throughout the follow-up period - Micropulsed diode gave significant reduction in retinal thickness in patients with focal macular edema - Laser-induced retinal damage (LIRD) noted -Eyes with residual DME treated with green mETDRS Luttrull et al Retrospective review of patients treated from 2000-2003 VA stable or improved in 85% (51) (2005) - Primary outcome measures: VA, FA leakage, and CSME - CSME decreased in 96% and resolved in 79% status - First without LIRD lesions. Undetectable - Follow-up: 3--29 months, mean 12.2 months ophthalmoscopically or angiographically - 5% DC throughout follow-up -810nm - Focal and diffuse DME -Fixed laser parameters used in all patients - Managed with SDM alone -First designed / intended to avoid LIRD -Pts treated between 2000-2003 -First to employ “low-intensity/high-density” “SDM” - Pre-OCT era technique Luttrull and Prospective follow up Overall reduction of macular thickness of 24% Spink -First report of OCT (time-domain) of subthreshold laser - 11 eyes with persistent or recurrent CSME (55) (2006) -15% DC were most improved (59% reduction of macular -810nm thickness) - High-density / low-intensity technique - Only report using 15% DC without LIRD -Fixed laser parameters used in all patients - OCT done at 1, 4, 12 weeks Sivaprasad et Non-comparative case-series - VA stable or improved in 84% in the first year, al (85) (2007) - 3-year follow-up maintained in the second year - Outcome measures: visual outcome and angiographic - By 3rd year, 92% maintained VA CSME status - More patients needed supplementary - 15% DC treatment in the 3rd year than in the 2nd year -810nm - CSME decreased in 92% and resolved in 88% in - Conventional (“low density”) grid technique the 1st year -Titrated laser parameters - 92% complete resolution by the 2nd year - By 3rd year; 28% had recurrent CSME - LIRD present Figueira et al Prospective randomized, controlled, double- masked trial No statistically significant difference in VA, (21) (2008) - Compared micropulsed diode/ argon green contrast sensitivity, and retinal thickness - 15% DC between the two groups -810nm - LIRD from MP - Conventional (“low density”) grid technique - Laser scarring much more apparent with argon -Titrated laser parameters laser compared to micropulsed diode (59% vs -LIRD considered prerequisite to effective treatment 13.9%)
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Study design Prospective, randomized trial - Follow-up: 5 months minimum - Main outcome measures: VA and macular thickness by OCT - First to report 5% duty cycle (DC) -810nm - Very long exposure duration (3.0 sec) - Conventional (“low density”) grid -LIRD considered prerequisite to effective therapy -Titrated laser parameters
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Authors/Year Laursen et al (43) (2004)
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- Outcome measures: VA, color fundus photographs, OCT, and contrast sensitivity - Follow-up: 12 months
Randomized controlled trial comparing SDM to mEDTRS
SDM superior to mETDRS
(91) (2010)
-MP fixed laser parameters used in all patients
-Both reduced central foveal thickness
-5% DC
-No LIRD with SDM by FAF
- Evaluated by microperimetry and FAF before / after
-LIRD with mEDTRS
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-Microperimetry worse after mETDRS; better after SDM
Randomized controlled masked single center clinical trial
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- New DME VA 20/40-20/400
-3 treatment arms: mETDRS; conventional (“lowdensity”) MP grid; high-density confluent MP -15% MP DC
High density MP grid superior to mETDRS -mEDTRS and conventional grid MP same reducing macular thickness -Conventional grid MP better VA than mEDTRS -High-density grid significantly better macular thickness reduction (avg 154um) and VA improvement (0.25 log MAR).
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-Titrated MP laser parameters
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-12 month follow up
-LIRD in all treatment arms
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- First report of SDM long-term safety -Compared LIRD risk of 5%, 10%, and 15% MP DC
Demonstrated high risk of LIRD if DC > 5% (p=0.0001) -All LIRD present at first follow up. No subsequent lesions -Computational tissue temp modeling corroborates clinical LIRD risk and efficacy findings
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Luttrull et al (56) Retrospective chart review eyes treated 2000-2010 (2012) - 212 eyes with DME and 40 with BRVO/ME
- Safety follow up: 3-120 months, median 47 months
- Reviewed 62 eyes evaluated before and after SDM with SD-OCT; median follow up 12 mos
- Computation tissue temperature modeling of MP laser parameters -
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- First reported case of transfoveal SDM for DME
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Luttrull and Sinclair (54) (2014)
Review paper of MP in DME
Retrospective review of transfoveal SDM in patients with fovea-involving DME and pre-treatment VA 20/20-20/40
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Luttrull and Dorin (49) (2012)
-First series report of transfoveal laser for DME (single case reported by Luttrull and Dorin 2012) -810nm
-5% DC / SDM technique
-Fixed laser parameters used in all patients -Two treatment centers
- If presentation VA > 20/50, SDM used alone -If presentation VA < 20/40, combo therapy -No outcome difference between SDM mono vs. combo therapy
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-First report of MP (SDM) combination (anti-VEGF) therapy
-By SD-OCT, central foveal thickness (P=0.04) and maximum macular thickness (P<0.0001) improved
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-First report of Spectral domain OCT and FAF of subthreshold laser
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-Mechanisms of sublethal laser proposed -Subthreshold laser platforms compared -New sublethal laser applications predicted -Use of sublethal laser as preventive treatment in DR recommended
No adverse treatment effects -No LIRD -LogMAR VA and macular thickness by SD-OCT both significantly improved
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-39 eyes of 27 patients -20 eyes > 20/25 prior to treatment RCT single center comparative study of 577nm and 810nm MP for center-involving DME
(90) (2015)
577 and 810 both effective
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-No difference all outcome measures -SDM technique
-53 patients, 6 months follow up -Evaluated by SD-OCT, FAF, microperimetry Meta analysis of subthreshold diode micropulse laser vs. conventional photocoagulation for DME
Six RCTs were selected for this meta-analysis, including 398 eyes (203 eyes in the subthreshold MP laser group and 195 eyes in the conventional laser group).
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-No LIRD in either group -Fixed laser parameters used in all patients
(14) (2016)
Visual results of subthreshold MP superior to conventional laser
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Reduction in macular thickness by OCT same
Legend: VA = visual acuity; DC = duty cycle; LIRD = laser-induced retinal damage; ETDRS = Early Treatment of Diabetic Retinopathy Study; FA = fluorescein angiography; CSME = clinically significant macular edema; Pts = patients; SDM = low-intensity / high-density subthreshold diode micropulse laser; OCT = optical coherence tomography; MP = micropulse; FAF = fundus autofluorescence photography; mEDTRS = modified EDTRS; DME = diabetic macular edema; BRVO = branch retinal vein occlusion; mos = months; SD-OCT = spectral domain optical coherence tomography; combo = combination; DR = diabetic retinopathy; RTC = randomized clinical trial.
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Table 2: Studies on use of micropulse laser in proliferative diabetic retinopathy Study design - Prospective, interventional, non-comparable case-series - 13 patients with PDR - 39 patients with ME secondary to DR or BRVO - Patients with PDR had PRP and those with ME had grid laser photocoagulation - Clinical and angiographic assessment at 3 and 6 months -MP used to in high-duty cycle / high-intensity to create retinal burns -LIRD considered prerequisite for effective therapy
Results - 10/13 patients with PDR (77%) showed some regression of new vessels at 6 months - 22/39 patients with ME had resolution of DME at 6 months - In DME patients, the VA was maintained in 27 (69%) and improved in 11 (28%) - Extensive LIRD in all eyes
Desmettre et al (18) (2006)
- 6 patients with PDR or SNPDR -Prior to conventional continuous wave frequency doubled Nd:YAG (532 nm) PRP, repetitively pulse diode photocoagulation was performed in a small region of each patient’s superior retinal periphery. Six parallel rows of 10 diode laser burns were made. Each diode laser exposure was 125 mm in retinal diameter and 0.2 seconds in duration. Repetitively pulse diode photocoagulation was performed with 500 Hz, 0.3 ms micropulses (15% duty factor) in 0.2 second exposures. -The minimal power needed for visible continuous wave diode laser photocoagulation was determined from two adjacent rows of laser lesions. -The minimal power needed for visible diode micropulse photocoagulation was determined from four additional adjacent rows of laser lesions. -Red-free photographs and fluorescein angiograms were obtained immediately and 6 days after laser therapy to classify lesions as photographically or angiographically ‘‘visible’’ or ‘‘subvisible.’’ -LIRD considered prerequisite for effective therapy
-Visible diode laser lesions could be obtained in all patients with CW photocoagulation and 5 of 6 patients with micropulse treatment
- Retrospective chart review of 99 eyes of 69 patients undergoing MP laser PRP - Range of disease (from severe NPDR to severe PDR - Outcome measures: VA and end points (the occurrence of vitreous HGE or the need for vitrectomy) - Follow-up: mean 1 year (range 0.3--2.7 year). -Use of high-density treatment strategy -15% DC required due to larger peripheral spot and laser power limitations -Intent to avoid any LIRD
- Overall VA remained unchanged throughout follow-up and the proportion of eyes with excellent VA of 20/30 or better increased from 39% to 48% - Probability of treatment failure at 12 months: 12.5% for vitreous HGE and 14.6% for vitrectomy, comparable to conventional PRP. - No treatment complications observed - No LIRD detectable clinically or by FA - Minimal pre retinal fibrosis and membrane contraction. - Attributed to absence of clinical
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Authors/Year Moorman and Hamilton (62) (1999)
-The laser energy needed for visible CW and micropulse lesions was almost same.
Luttrull et al (52) (2008)
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- There was no significant difference in the power required to produce photographically and angiographically visible lesions.
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inflammation -No de novo DME or aggravation of existing DME -Reduced progression from SNDPR to PDR reduced from expected 50% to 7.9% (P=0.0001)
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Table 2 Legend: PDR=proliferative diabetic retinopathy. BRVO=branch retinal vein occlusion. DME=diabetic macular edema. DR=diabetic retinopathy. NPDR=non-proliferative diabetic retinopathy. SNPDR=severe non-proliferative diabetic retinopathy. MP=micropulse. PRP=panretinal photocoagulation. LIRD=laser-induced retinal damage. VA=visual acuity. Hz=Hertz. CW=continuous wave.
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S0039-6257(17)30166-2
DOI:
10.1016/j.survophthal.2017.09.008
Reference:
SOP 6757
To appear in:
Survey of Ophthalmology
Received Date: 20 May 2017 Revised Date:
13 September 2017
Accepted Date: 22 September 2017
Please cite this article as: Chhablani J, Roh YJ, Jobling AI, Fletcher EL, Lek JJ, Bansal P, Guymer R, Luttrull JK, RESTORATIVE RETINAL LASER THERAPY: Present state and future directions., Survey of Ophthalmology (2017), doi: 10.1016/j.survophthal.2017.09.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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RESTORATIVE RETINAL LASER THERAPY: Present state and future directions.
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Jay Chhablani,1 Young Jung Roh, 2 Andrew I. Jobling,3 Erica L. Fletcher,3 Jia Jia Lek, 4 Pooja Bansal,5 Robyn Guymer,4 Jeffrey K
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Luttrull, 7,8
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1. L.V.Prasad Eye Institute, Kallam Anji Reddy Campus, Banjara Hills, HYDERABAD - 500 034
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2. Department of Ophthalmology and Visual Science, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic
University of Korea, Seoul, Korea 10, 63-ro, Yeongdeungpo-gu, Seoul 150-713, Korea e-mail: [email protected]
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3. Department of Anatomy and Neuroscience. The University of Melbourne, Parkville 3010 Victoria, Australia.
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4. Centre for Eye Research Australia, University of Melbourne, Department of Surgery (Ophthalmology), Royal Victorian Eye
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110 029, India
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5. Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi -
6. Ventura County Retina Vitreous Medical Group, 3160 Telegraph Road, Suite 230, Ventura, California 93003
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and Ear Hospital, Victoria, Australia
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Corresponding author: Jeffrey K Luttrull, MD. Ventura County Retina Vitreous Medical Group, 3160 Telegraph Road, Suite 230,
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Ventura, California 93003. Ph 805.650.0664. Fax 805.650.0865. Email [email protected] Web
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www.venturacountyretina.com
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ABSTRACT
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Because of complications and side effects, conventional laser therapy has taken a back seat to drugs in the treatment of
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macular diseases. Despite this, research on new laser modalities remains active. In particular, various approaches are being
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pursued to preserve and improve retinal structure and function. These include micropulsing, various exposure titration algorithms
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and real-time temperature feedback control of short pulse continuous wave lasers, and ultra-short pulse nanosecond lasers.
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Some of these approaches are at the pre-clinical stage of development, while others are available for clinical use. Cell biology is
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providing important insights into the mechanisms of action of retinal laser treatment. We outline the technological bases of
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current laser platforms, their basic science, therapeutic concepts, clinical experience, and future directions for retinal laser
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treatment.
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KEY WORDS: Laser photocoagulation; Subthreshold Laser; Micropulse Laser; Retinal Laser; Microsecond Laser; Panretinal
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Photocoagulation; PASCAL; NAVILAS; Pattern Scanning Lasers; Nanosecond Laser; Selective Retina Therapy; Endpoint
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Management; 2RT
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INTRODUCTION
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Laser photocoagulation has been used for decades to treat a number of common retinal disorders. These include diabetic
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macular edema (DME), proliferative diabetic retinopathy (PDR), macular edema secondary to branch retinal vein occlusion
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(BRVO), retinal ischemia from vasculitis, retinal vascular occlusion, central serous chorioretinopathy (CSR), ablation of age-
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related choroidal neovascularization (NAMD), and retinopexy for retinal tears. The advent of anti-vascular endothelial growth
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factor (anti-VEGF) therapy saw the role of laser therapy diminish. This occurred for two principal reasons: the risks and adverse
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treatment effects associated with conventional photocoagulation and the remarkable effectiveness of the new pharmacologic
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agents. Despite this, considerable progress has been made in developing new laser systems and modes of treatment to improve
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their safety and effectiveness and increase their clinical utility. Following a brief review of laser principles and technology, each
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current retinal laser platform and treatment approach will be discussed. These approaches are at times at odds. While some
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advocate treatment sublethal to the retina, others employ selective retinal damage; however, the commonalities are also notable.
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All seek to eliminate or reduce retinal damage, to expand treatment indications, and to improve patient outcomes by avoiding
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conventional retinal photocoagulation.
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REVIEW OF RETINAL LASERS AND THEIR EFFECTS
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Conventional continuous-wave (CW) laser retinal photocoagulation (RPC) is a photothermal destructive therapy where the
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photoreceptor/retinal pigment epithelium (RPE)-choriocapillaris complex is coagulated with visible burns, with elevation in tissue
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temperature mediating the therapeutic effect. The heat created by RPC spreads outward from the burn site in the RPE and/ or
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choroid. The ‘‘grayish-white’’ endpoint of RPC signifies that the thermal wave has reached the overlying neurosensory retina with
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a temperature high enough to coagulate proteins in the naturally transparent neural retina, making it opaque by scattering light.
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(74) Becaue of the intensity of retinal irradiation, RPC may be painful despite use of topical anesthetic drops, requiring local
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anesthesia. Alternatively, treatment may be divided into stages over an extended time to minimize treatment-related pain and
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postoperative inflammation. Because RPC typical employs visible light wavelengths, RPC often produces uncomfortable flashes
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of light as laser spots are applied. Inflammation resulting from photocoaulative tissue destruction may cause reduction in visual
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acuity, usually transient, following RPC. Such factors may increase patient anxiety and reduce compliance with the prescribed
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treatment regimen. All complications and adverse treatment effects of RPC are attributable to laser-induced retinal damage
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(LIRD). These include progressive scar expansion, visual field defects, alterations in color vision, reduced contrast sensitivity,
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subretinal fibrosis, and choroidal neovascularisation. (26, 82, 90)
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CURRENT RETINAL LASER MODES
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Laser is an acronym for light amplification by stimulated emission of radiation. All lasers are comprised of three essential
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components: a lasing material, a pump source to introduce energy into the lasing material, and an optical cavity with reflectors
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for light amplification. Population inversion occurs when energy from the pump source is introduced into the lasing material,
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which excites electrons in the lasing material’s atoms and causes them to go from a steady, low-energy state to an unstable,
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higher-energy level. (83) Decay (the return of electrons to the steady state energy level) releases photons of the wavelength of
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the energy transition that have the ability to travel in phase in the same direction. Amplification of this coherent radiation occurs
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as photons travel back and forth in phase in the optical cavity through the lasing material between a total reflecting mirror and a
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partial reflecting mirror. When sufficient energy has built up, this laser light may be released through the partially reflecting mirror
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and directed toward the retina, effecting treatment.
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Some important definitions are:
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Power - The rate at which energy is emitted from a laser.
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Population inversion: The state present within the laser optical cavity (resonator) where more atoms exist in unstable high-energy
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levels than their normal resting energy levels.
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Pulse: The brief span of time for which the focused and scanned laser beam interacts with a given point on the target (usually
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from milliseconds to nanoseconds)
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Q-Switch: An optical device that controls the storage or release of laser energy from a laser optical cavity. Q-switching is a
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means of creating very short pulses (5-100 ns) with extremely high peak powers. Q stands for quality.
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Titration: Adjustment of laser dose based on patient response. Dosages are traditionally adjusted by the operating surgeon by
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directly visualizing retinal laser effects on the retina until the desired level of intensity is achieved.
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Duty cycle : “Pulsed” lasers apply laser exposure in trains of short burst, rather than the continuous beam of conventional lasers.
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The duty cycle is defined as the length of time of “power on” divided by the total time the laser is used. For example, the duty
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cycle of a conventional laser is 100% because, during the laser exposure, the laser beam is on continuously. A 5% duty cycled
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pulsed laser means that each burst of energy released (a “micropulse”) is “on” for 100 µs followed by 1900 µs in the “off” mode.
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Lasers can be used in distinct modes of operation depending on duration of laser emission. The most important are
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continuous wave (CW operation) refers to a laser that produces a continuous output beam, causing a rapid temperature rise.
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Quasi-continuous-wave operation (quasi-CW operation) is when the pump source is switched on only for short time intervals to
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minimize heat transfer.
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Gain-switched operation: gain switching means that the pump source is turned out only for very short time intervals in order to
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obtain short pulses.
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Q-switched operation: In a Q-switched laser, the population inversion is allowed to build up by introducing loss inside the
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resonator, which exceeds the gain of the medium. The intracavity losses are modulated, allowing lasing to begin which rapidly
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obtains the stored energy in the gain medium so that the laser emits energetic pulses.
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Mode-locked operation: Mode-locking is an optical technique by which a laser can be made to produce pulses of extremely short
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duration, on the order of picoseconds (10−12 s) or femtoseconds (10−15 s). Mode-locked lasers employ resonant modes of the
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optical cavity which can affect the characteristics of the output beam. When the phases of different frequency modes are
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synchronized, or "locked”, the different modes will interfere with one another to generate a beat effect. The resultant laser output
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is regularly spaced pulsations. A mode-locked laser can deliver higher peak powers than the same laser operating in the Q-
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Evolution of Retinal Laser Photocoagulation
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The era of photocoagulation was born in 1956 when Meyer-Schwickerath and Littman worked with Zeiss to design the first
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Xenon-arc coagulator. (61) In 1960, Maimann then invented the ruby laser, (58) a solid-state laser with wavelength of 694 nm
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emitted short pulses (less than 1 millisecond). The ruby laser provided a more controlled delivery of energy, allowing
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ophthalmologists to manipulate and more precisely target light beams, creating small chorioretinal scars and reducing the risk of
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damage to surrounding tissues compared to the Xenon arc lamp. Though this wavelength transmits well through ocular media
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and is absorbed efficiently by the retinal pigment epithelium and choroid, it was poorly absorbed by blood, preventing effective
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treatment of vascular lesions.
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Discovery of the Argon laser in 1964 by Bridges provided a new tool with emission in the blue (488-nm) and green (514-
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nm) range of the spectrum. (8) Subsequently, Krypton red and tuneable dye gas lasers included yellow and orange wavelengths.
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Eventually, shorter wavelengths in the blue range were abandoned to reduce damage to the neurosensory retina. Gas lasers
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suffered from significant impracticalities including large size, the need for water cooling, high voltage electric power, and gradual
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degradation and power loss. Today, the more commonly used frequency doubled Nd:YAG and diode lasers use solid-state
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platforms that utilize crystals and semiconductors, respectively. These current lasers are compact, portable, highly reliable, and
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long lasting. (83)
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THE MECHANISM OF RETINAL LASER TREATMENT
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Historically, the 4 main hypotheses offered to explain the mechanism of retinal laser action accepted LIRD as the necessary and
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sufficient cause of the therapeutic effects. These included reduction in oxygen consumption and thus metabolic stress by thermal
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destruction of the retina and / or retinal photoreceptors; photoablative debulking of pathologic retina by RPC, improved choroidal-
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retinal oxygenation by photocoagulation-induced retinal thinning, and/or retinal heat-shock protein (HSP) activation. (54) Despite
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consideration of these hypotheses for over 50 years, none was proven. Shorter wavelength lasers (below 550nm) were found to
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produce photochemical damage to the neurosensory retina without improving outcomes. Thus, the therapeutic effects of retinal
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laser treatment appeared to be entirely thermal in origin; however, it was not until demonstration of clinically effective retinal laser
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treatment designed to be reliably sublethal to the retina that the long-held belief in the therapeutic necessity of LIRD was called
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into question. This effectively eliminated the theories of retinal laser action that invoked the need for photocoagulation. Of the 4
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primary theories of retinal laser action, only thermal - but sublethal - retinal HSP activation remained. (4, 11, 14, 24, 26, 31, 44,
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47, 48, 51, 52, 54, 59, 62, 74, 77, 82, 90, 98)
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In vitro testing has subsequently confirmed thermal laser induced HSP activation in the retina surviving laser exposure as the
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likely key trigger of the therapeutic response. This demonstrated translational replacement of the HSPs used in the stress
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response in the specific patterns predicted and depicted by Luttrull and Dorin in 2012. (11, 31, 49, 87) Application of scaling law
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analysis to the biophysics of laser-retinal interactions indicates a strong association between thermal laser effects and HSP
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activation as the initiating step in a cascade of reparative phenomena improving RPE function, retinal autoregulation, reparative
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acute inflammation, reduced markers of chronic inflammation, and immunomodulation. (11, 25) In a recent murine model,
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micropulsed 810nm laser was applied at sublethal intensity to the RPE, producing increases in mRNAs for Hspa1a, Hsp90aa1,
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Cryab; Hif1a, Cxcl12, Hspa1a Ccl-2, Il1-β, IFN-γ and Il-6 between 2 to 24 hours post treatment in the RPE-choroid. (11) One and
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two weeks following sublethal micropulse treatment of the RPE one eye, recruitment of bone-marrow stem cells to the RPE of
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both eyes was documented, showing that sublethal thermal photostimulation of the retinal pigment epithelium can produce a
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systemic immunologic response. (11) This latter observation may account for the common observation of bilateral improvements
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after unilateral laser treatment. (27) In sum, all therapeutic retinal laser effects are in fact “subthreshold” and derived from retina
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affected, but not killed, by retinal laser exposure. (49)
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The biophysics of various modes of retinal laser delivery dictates four basic classes of potentially therapeutic retinal laser effects. Each has been well demonstrated and documented clinically and in laboratory studies:
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1. Retinal photocoagulation (RPC): In RPC, the targeted tissue is thermally destroyed by CW or high-duty cycle micropulsed
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laser. At the site of laser application, retinal function is lost, and the destroyed tissue does not participate in the therapeutic
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effect. Instead, collateral heating of surviving tissue at the margins of the RPC lesion indirectly produces the desired therapeutic
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effects, as well as healing the laser-induced retinal damage.
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2. Selective retinal ablation (SRA): Short and ultra-short pulsed CW lasers generated by gain-locked, Q-switched, and mode-
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locked devices. The Arrhenius integral for cell death is exceeded before the threshold of the integral for HSP activation is
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reached. The RPE is selectively ablated without significant collateral thermal or physical effects. Thus, like RPC, the therapeutic
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effect of SRA is produced indirectly by the healing response and inflammation that occurs in response to the RPE ablation as
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cells adjacent to the wound respond by sliding to fill and repair the laser-induced RPE defect. Unlike RPC, there is effectively no
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therapeutic contribution from sublethal stimulation of tissue adjacent to the laser spot.
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3. Simple retinal photostimulation (SRP): CW laser treatment at very low power can be used to stimulate the RPE sublethally.
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Thus, in SPR therapeutic HSP activation is direct. Because the therapeutic window of CW laser is extremely narrow (10mW) and
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human RPE pigment heterogeneity is high (compared to rabbits and mice), safe, effective, predictable, and reliably sublethal
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SRP is difficult. Currently, attempts at algorithmic titration termed “end-point management” and real-time photoacoustic tissue
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temperature modulation seek to improve the safety and effectiveness of CW laser by improving targeting of the narrow
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therapeutic window. (46, 47, 76, 77) Because the safe temperature rise of sublethal CW laser is relatively gradual (1000 C / sec),
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various studies suggest it may not be an especially efficient stimulator of RPE HSPs. (13, 29, 45, 64, 65)
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4. Amplified retinal photostimulation (ARP): Low-duty cycle micropulsed laser is used to directly stimulate RPE HSP activation
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sublethally. This mode is exemplified by low-intensity / high-density subthreshold diode micropulse laser (“SDM”). Because the
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therapeutic range (TR, the range between the initiation of a biologic effect to the 50/50 burn risk threshold) of SDM is broad (over
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3 Watts currently; increasable to 25 Watts or more) treatment titration (associated with LIRD in all published studies) is
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unnecessary. Because the known maximum variation of human RPE pigment density is 1.5 – 2.0x “normal”, all patients fall
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within the broad therapeutic range of ARP. (25, 46, 47, 49, 51, 54, 56, 87, 88) Thus, ARP can be performed with fixed laser
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parameters known to be both safe and effective. Absent LIRD and its associated inflammation and loss of retinal function, there
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is a complete absence of known adverse treatment effects, prompt (within 24 hours) improvements in visual function and
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electrophysiology, and long-term clinical benefits in all reported applications. The ARP / SDM treatment strategy of “low-intensity
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/ high-density” treatment application echoes the Early Treatment of Diabetic Retinopathy Study (EDTRS) finding that increased
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treatment intensity (and LIRD) is associated with poorer visual results and increased adverse treatment effects, while increased
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treatment density is associated with improved anatomic results. (6, 14, 21, 24, 43, 44, 51, 54, 56, 59, 67, 74, 84, 85, 91, 92). The
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safety of ARP allows confluent (highest-density) treatment application, maximizing visual and anatomic results. (51) For
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example, ARP, as transfoveal SDM, has been reported to significantly improve both visual acuity and macular thickness with
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eyes with center-involving DME and excellent (20/40 or better) pre-treatment visual acuity, without adverse treatment effects.
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(44, 54) The abrupt but sublethal temperature changes of the micropulsed laser (100,0000 C/ sec) may be especially efficient
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triggers of RPE HSP activation (thus, “amplified” retinal photostimulation) capable of increasing the effectiveness of HSP
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activation by magnitudes compared to SRP and broadening the therapeutic range by lowering the HSP activation threshold. (19,
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25, 48)
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We will now examine the above concepts by reviewing each current retinal laser platform, its clinical application, and current
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laboratory research. Thereafter, an informed look at the future of retinal laser treatment will be offered.
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MICROPULSE LASER PHOTOCOAGULATION
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In 1990, Pankratov reported development of a new laser modality designed to deliver laser energy in short pulses
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(“micropulses”) rather than as a continuous wave. (68) Micropulse technology is a laser delivery method that added a new
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dimension of control over laser output, facilitating tissue-sparing applications. Unlike conventional continuous wave laser
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photocoagulation, micropulse technology finely controls thermal elevation by “chopping” a CW beam into an envelope of
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repetitive short pulses. Repetitive short “micro” pulses can produce higher peak tissue temperatures and more abrupt tissue
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temperature changes (100,0000 C/sec) compared to CW lasers (1000 C/sec), while pulse spacing permits the tissue to cool
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between pulses, minimizing heat buildup. By shortening laser pulses, the temperature rise occurs with increasing selectivity in
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the RPE. (19) The main determinant of average tissue temperature rise is the duty cycle (the frequency of the train of
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micropulses), dictating the length of time between pulses. (19, 56) The lower the duty cycle, the longer the off time between
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pulses (lower repetition rate) and the less heat build-up. If the off time exceeds the thermal relaxation time of RPE melanin (the
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target molecule), the average tissue temperature rise in the RPE during micropulsed laser application can be maintained below
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levels lethal to the cell. Clinical studies and computer modeling have demonstrated that treatment safety is maximized by use of
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5% or lower duty cycles.
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determinant of laser efficacy is peak temperature. By minimizing average tissue temperature heat buildup with a low duty cycle,
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micropulsing can produce higher sublethal peak temperatures than CW lasers. Thus, micropulsing (MP) is both safer and more
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effective. (19, 25, 56) Numerous studies have shown MP is effective at sublethal irradiation levels, offering a tissue-sparing
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Higher duty cycles rapidly take on the clinical characteristics of CW lasers. Another important
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solution for the treatment of various retinal diseases. Treatment is painless, requiring only topical anesthesia. Following MP laser
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patients may report improved visual function within hours of treatment, and the risk of treatment-associated visual loss from
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LIRD and resultant inflammation can be avoided. (19, 51, 54, 56)
CLINICAL APPLICATIONS OF MICROPULSED LASERS
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Diabetic macular edema
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The application and development of subthreshold / sublethal retinal laser treatment has centered on the treatment of diabetic macular edema (DME). The ETDRS showed that increased treatment intensity was associated with more adverse
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treatment effect,s, that increased treatment density improved clinical results, that grid treatment was as effective as focal
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treatment; and that the location and extent of macular angiographic leakage did not correlate with clinical outcomes. (74) With
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this knowledge, practitioners began to move to less damaging retinal laser treatment, primarily by reducing treatment intensity.
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LIRD, however, was universally believed to be essential to obtain a therapeutic effect, and the risks and limitations of treatment
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persisted. (21, 24, 59, 62)
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In 1997, Friberg and Karatza first reported clinical application of MP 810nm diode laser therapy for DME. Since LIRD was still
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presumed to be necessary to achieve effective therapy, micropulsing was used to reduce (“invisible”), but maintain, LIRD. This
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was done by use of high duty cycles (15% or more) to enhance the photocoagulative potential of the MP 810nm laser. (19, 21,
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24, 62, 67, 84) In 2004, Laursen reported use of the 810nm laser using a lower 5% duty cycle; (43) however, long exposure
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durations (3.0 seconds) were employed, again with the intent of causing LIRD. Thus, the presumption that LIRD was essential
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for a therapuetic effect perpetuated the limitations and adverse treatment effects of associated with conventional retinal
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photocoagulation.
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Year 2000 marked a significant change in the conception and application of retinal laser therapy. (51) For the first time retinal
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laser treatment was performed with the intent of preventing LIRD; that is, treatment sublethal to the RPE. This was done by
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exploiting attributes unique to the MP laser (MPL). Rather than using high duty cycles or long exposures to cause LIRD, a low
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(5%) duty cycle was employed with new parameters intended to avoid retinal damage. (56) The safety afforded by avoidance of
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LIRD allowed a second, simultaneous and critical innovation: complete and contigous laser coverage of all areas of retinal
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pathology. (51) By so doing, broad recruitment of the target tissue and primary disease mediator – the RPE – was achieved,
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maximizing therapeutic effects. With this new approach, called “low-intensity / high-density subthreshold diode micropulse laser”
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(SDM), effective and reliably sublethal retinal laser treatment could be done without any LIRD or adverse treatment effects. The
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SDM strategy of high-density sublethal retinal laser application defines modern retinal laser therapy.(6, 14, 41, 49, 51, 84)
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Since Friberg, many studies have reported the efficacy of MPL for DME (Table 1). Gradually, the intent of causing LIRD via high
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duty cycles and use of conventional application techniques has been replaced by the low-intensity (sublethal) / high-density
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(confluent treatment of broad areas) treatment paradigm. (56) Studies of MPL for DME show that increased treatment density
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maximizes macular thickness reduction, while avoidance of LIRD maximizes visual acuity improvement. (14, 44, 51) Controversy
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exists regarding use of MPL as a first line treatment, or secondary to drug therapy; however, there is wide agreement on two key
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points: the effectiveness of micropulse laser as primary monotherapy in eyes with macular thickening < 400um and the
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superiority visual results of MPL to conventional laser techniques such as modified EDTRS photocoagulation. (6, 14, 44) While
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Sivaprasad and associates reported a 28% recurrence rate of DME within 3 years of initial MPL treatment, avoidance of LIRD
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makes it possible to repeat treatment as necessary to prevent visual loss. (83) The reliable safety of SDM permits early
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treatment of DME, including transfoveal treatment for center-involving DME with good visual acuity, reducing the risk of visual
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loss, and minimizing the need for intensive and expensive intravitreal drug therapy. (51, 54, 56, 91) (Figure 1)
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Proliferative diabetic retinopathy
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Moorman and Hamilton used high-duty cycle MPL as “minimal intensity” panretinal photocoagulation (PRP) for proliferative
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diabetic retinopathy (PDR), with the goal of maintaining the LIRD thought at the time necessary for effective therapy, while
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reducing the severity of photocoagulative retinal damage and associated adverse treatment effects. In 10/13 eyes treated, they
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noted regression of neovascularization. (62) The only report of sublethal panretinal micropulse laser (SDM PRP) to date
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described 99 eyes (61 with PDR and 38 severe non-proliferative DR) of 69 consecutive patients treated between 2000-2003,
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followed for a median of 12 months. (52) Overall VA remained unchanged, but the proportion of eyes with excellent VA (20/30 or
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better) increased from 39% to 48%. Because of large peripheral retinal laser spot sizes (1mm) and 810nm diode laser power
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limitations (2.0 Watt maximum), a 15% duty cycle was employed to achieve a therapeutic irradiance. Despite the still low
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irradiance levels, equivalent to just 18x American National Standards Institute “Maximal Permissible Exposure” levels (ANSI
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MPE), treatment was found to be effective and comparable to conventional PRP. (51, 56) Despite the high duty cycle, no LIRD
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was observed. SDM PRP was performed in a single session with topical anesthesia, and no patient reported postoperative pain
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or loss of visual acuity, accommodation, night vision, or visual field. In the absence of LIRD, there was no postoperative
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inflammation, and no eye demonstrated development or worsening of macular edema postoperatively. The absence of
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inflammation was credited with a notably quiet postoperative clinical course, with minimal preretinal fibrosis and membrane
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contraction and no apparent inducement of posterior vitreous detachment. No eye progressed to a surgical traction retinal
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detachment or neovascular glaucoma. Only 3 of 38 eyes with severe non-proliferative diabetic retinopathy (7.9%) progressed to
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PDR. Compared to the expected annual rate of 50%, this reduction in DR progression was significant (p=0.0001). (52) Table 2
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shows the summary of studies evaluating micropulse laser in PDR. (Figure 2-4)
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Central serous chorioretinopathy
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MPL was first reported for the treatment of CSR by Lanzetta, et al, in 2003. (42) Since then, over 30 studies of MPL for CSR
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have been published (www.ncbi.nlm.nih.gov/pubmed/), including retrospective and randomized controlled studies of various
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sizes employing a variety of different laser wavelengths, treatment parameters, treatment protocols, and patient populations. (57,
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60) Despite such heterogeniety, in all studies MPL for CSR has been found to be effective: comparable to half-fluence
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photodynamic therapy, superior to anti-VEGF therapy, and safe. Comparison of these studies suggests that, reflecting the prior
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discussion, the effectiveness of MPL for CSR parallels treatment density, while safety parallels treatment intensity. The safety of
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the SDM strategy (low-duty cycle with fixed treatment parameters) allows reliably safe treatment of subfoveal leaks, early
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treatment, and repeat treatment should clinical needs dictate. (57, 60) Nearing completion is the PLACE trial (clinicaltrials.gov:
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NCT01797861), a randomized prospective clinical trial in the Netherlands comparing half-dose verteporfin photodynamic therapy
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with MPL for central serous choroiretinopathy. (7) Refecting long clinical experience with MPL, the PLACE trial employed fixed
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laser parameters for treatment of all patients to maximize treatment safety; however, in a departure from precedents, the PLACE
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trial also elected to use twice the power of any prior study for low-duty cycled 810nm MPL. The reason for this decision is
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unclear, as the clinical effectiveness and safety of lower laser powers has been well established. While a goal of treatment in the
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PLACE trial is to avoid ophthalmoscopically visible laser lesions at the time of treatment, intra-treatment ophthalmoscopy may
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significantly underestimate actual LIRD. As doubling of the laser power increases the risk of retinal damage, it will be interesting
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to see how these treatment parameters fare in a large, although generally lightly pigmented, population. (7, 56)
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Branch Retinal Vein Occlusion
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Four studies have described the use of micropulse laser in the treatment of macular edema secondary to branch retinal vein
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occlusion (BRVO). Parodi and coworkers found no difference in results of subthreshold conventional-density grid laser treatment
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and RPC in terms of resolution of macular edema and improvement of visual acuity, although photocoagulation worked more
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quickly. (70)
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grid laser treatment in combination with intravitreal triamcinolone injection compared RPC for BRVO. (71) Luttrull, et al, included
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eyes with macular edema due to BRVO in a larger study demonstrating the danger of macular micropulse laser employing duty
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cycles above 5%. (56) More recently, Inagaki, et al, reported effective control of ME with subthreshold micropulse laser in
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patients with persistent macular edema due to BRVO and visual acuity better than 20/40. (30) Because macular edema due to
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BRVO tends to be a chronically waxing and waning condition, the ability to perform periodic retreatment safety with micropulsed
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lasers may be an aid to clinical management.
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Age related macular degeneration
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York, Glaser, and Murphy used indocyanine green angiography-guided micropulse laser to safely close choroidal feeder vessels
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in neovascular AMD. (97) In 2015, reversal of tolerance to anti-VEGF drugs in neovascular AMD was reported using SDM. (48)
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Thirteen eyes, unresponsive to all anti-VEGF medications for at least 6 months and 4 consecutive injections of aflibercept, were
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treated by MPL. One month later, anti-VEGF therapy was resumed. After re-challenge and resumption of aflibercept, macular
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exudation resolved in 12/13 eyes. They report that reversal of drug tolerance in wet AMD by MPL was predicted by “Reset to
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Default” theory, which postulates activation of RPE heat-shock proteins as the initiating mechanism of retinal laser treatment. As
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the first report of drug tolerance reversal in medicine, these findings lend strong support to the reset postulate. (48)
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In 2016, Luttrull and Margolis reported “functionally-guided panmacular micropulse laser” as “retinal protective therapy” (RPT) in high-risk dry AMD and inherited retinopathies. (50) Patients were evaluated before and after SDM RPT by pattern
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electroretinography (PERG) and visual function tests. After SDM RPT, 139/158 eyes were improved by PERG (P= 0.0001). VA
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was unchanged, but macular sensitivity by microperimetry (40 eyes) and mesoptic contrast visual acuity (73 eyes) improved (P =
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0.0439, and P = 0.006, respectively). Despite these improvements in retinal and visual function, no change in retina morphology,
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such as drusen number, size or distribution, was noted. Eyes with the worst preoperative measures improved the most following
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SDM by all indices (P = 0.0001). This included eyes with extensive geographic atrophy. By maintaining improved retinal function
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guided by early and periodic electrophysiologic signals, rather than late imaging signals, the authors hope to reduce the long-
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term risk of vision loss. (48, 50)
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In a subsequent retrospective study of 454 consecutive eyes of 296 patients in the Age-Related Eye Disease Study
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(AREDS) treated with panmacular SDM for high-risk dry AMD and followed a minimum of 1 year (range 1-7 years, avg 2 years),
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the incidence of new CNV was found to be less than 1% per year. (1) This was despite an average patient age of 83 years and
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high independent risk factors including fellow eye CNV (26%), reticular pseudodrusen (38%) and AMD severity (78% AREDS
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categories 3 and 4), all significantly exceeding the AREDS. These findings suggest that panmacular SDM may reduce the
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incidence of CNV in dry AMD more than vitamin therapy alone. In addition, in 409 of these same eyes, best-corrected logMAR
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mesopic visual acuity (p < 0.0001) and visual fields (P=0.0007) were also improved following panmacular SDM. There were no
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adverse treatment effects or LIRD. These findings suggest that retinal and visual function testing may be useful surrogate
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indicators of longer-term treatment benefits (or risks). (Figure 5) (Luttrull JK, Sinclair SH, Elmann S, Glaser BM. Panmacular subthreshold
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diode micropulse laser (SDM) for high-risk dry AMD: CNV Incidence and Mesopic visual function. Abstract and free paper presentation, American Society
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of Retina Specialists, annual meeting, Boston, August 8, 2017).
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Inherited retinopathies
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In addition to PERG in dry AMD, Luttrull and Margolis also reported SDM for a small group of inherited retinal degenerations
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(IRD). (50) PERGs were improved after SDM in 10 eyes of 8 patients with retinitis pigmentosa (RP, 4 eyes), cone degeneration
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(CD, 3 eyes) and Stargardt disease (Starg, 3 eyes) (p=0.002). While eyes with AMD improved most by a low-contrast PERG,
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IRD eyes improved most by the widest-field (240) high contrast PERG protocols. In both AMD and IRD, measures of signal
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latency improved most significantly. The authors note that both the functional improvements and the distinct PERG responses in
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AMD vs. IRD were predicted by the reset theory of retinal laser action. (50) More recently, updated results including 24 control
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and 34 treated eyes with non-age-related retinal degenerations (26 with RP, 3 CD, 4 Starg, and 1 with vitamin A deficiency)
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showed improved retinal function by PERG (27/34 eyes; P = 0.0003) and visual function by automated perimetry (20/21 eyes,
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P<0.0001) (Luttrull JK. Panmacular subthreshold diode micropulse laser (SDM) retinal protective therapy in non-age related retinopathies. Abstract
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and free paper American Society of Retina Specialists, annual meeting, San Francisco, CA, August 2016).
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Micropulse laser for neuroprotection in primary open angle glaucoma (POAG)
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Just as the reset theory of retinal laser action has successfully predicted reversal of anti-VEGF drug tolerance in AMD, and
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improved retinal and visual function in dry AMD and inherited retinal degenerations, reset theory also predicted that SDM should
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be neuroprotective. All chronic progressive retinopathies are examples of neurodegenerative disease. The purest case may be
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POAG, where there is no clinically discernable retinopathy. Recently, a retrospective study reported 88 consecutive eyes with
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advanced POAG marked by glaucomatous optic neuropathy and/or visual field loss evaluated before and after panmacular SDM
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by visually evoked potentials (VEP) and mesoptic automated perimetry. After treatment, significant improvements in both VEP
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P1 amplitudes (P=0.001) and mesopic visual fields (P<0.0001) were documented. There were no adverse treatment effects.
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SDM is thus the first treatment reported to improve visual fields absent pressure lowering in POAG; and the first treatment
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reported to improve the VEP and produce clinical neuroprotective effects. (53) (Figure 6)
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Navigated Micropulsed Laser
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Improved accuracy, eye tracking, computer based planning, enhanced training and documentation are advantages reported for
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navigated laser photocoagulation using the semi-automated NAVILAS® device. (2, 15, 36, 40) Recently, NAVILAS® became
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available with 577nm yellow laser with microsecond (micropulse) technology. (2) The NAVILAS® allows detailed documentation
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of sublethal micropulse laser application, with various duty cycle options along with navigated ability. Such documentation could
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be useful especially while repeating the subthreshold laser. Initial reports using this system showed success in CSR with
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juxta/subfoveal leaks. (Figure 7)
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PATTERN SCANNING LASERS
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Historically, retinal laser machines project a single laser beam through a coupled slit lamp biomicroscopic delivery system. Laser
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spots are applied to the retina under the direct observation of the operating surgeon. The laser beam is directed with a hand-held
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joy stick that manipulates the fiber optic or a reflecting mirror in order to point the laser spot to the precise retinal location desired,
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aided by a sub-therapeutic “aiming beam”, visible to the surgeon at all times. If many laser spot applications are required,
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treatment can be facilitated by an automatic “repeat mode”that fires the laser continuously with depression of the foot pedal until
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the pedal is released. (41)
In 2005, Optimedica introduced the first partially automated retinal laser system, called the “pattern scanning laser”, or
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“PASCAL”. (5) The PASCAL allowed the operator to select from several small preset patterns of various shapes, and apply
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photocoagulation to the retina in these patterns with a single depression of the foot pedal. To cover larger treatment areas, these
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preset patterns are then serially redirected to different retina locations with a joystick, in the same way that manual lasers redirect
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single spots.
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In order to deliver preset 5 x 5 grids of 25 single sequentially placed shots of retinal photocoagulation safely (prior to
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patient movement or blinking), a high scanning speed, and thus low laser pulse duration, is required. The developers of the
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PASCAL theorized that the driving force for progression of DR was retinal oxidative stress caused by retinal photoreceptor
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oxygen consumption. According to this theory, effective treatment of DR required selective destruction of at least 30% of retinal
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photoreceptors. Thus, a short-pulse (10-20ms) duration CW 532nm laser was employed that could selectively destroy the outer
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retina within the time constraints of pattern application limited by patient fixation. (32, 33, 46)The pattern scanning laser has been
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reported to be comparably effective to conventional photocoagulation, but with less retinal damage, in the treatment of diabetic
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macular edema. (33)
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Because of the short pulse duration and limited heat-spread from the center of the photocoagulation spot, PASCAL PRP may be more comfortable for patients than conventional PRP. Possibly reflecting the dynamics of selective retinal ablation as
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described above, PASCAL photocoagulation has been reported to be less effective than conventional photocoagulation. (3, 13,
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29, 33, 64, 65) Increasing the treatment density of PASCAL treatment by 2- 3x, or more, compared to conventional
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photocoagulation, has been recommended to improve clinical results. (13) Reflecting the biophysics of SRA (discussed above),
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however, a recent report from the Diabetes Clinical Research Network found that, despite increased treatment density, the
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pattern scanning laser was less effective than ranibizumab or conventional panretinal photocoagulation for proliferative diabetic
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retinopathy. (3, 29)
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platforms designed for photocoagulation have been repurposed to perform sublethal treatment. This includes the pattern-
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scanning laser. (45) Confirming the ANSI MPE predicted narrow TR of 0.010 watts for CW lasers with in vivo animal studies of
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HSP activation, an algorithm called “end point management” (EPM) was created to aid PASCAL users attempting to avoid LIRD.
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(45, 46, 47, 88) With EPM, the surgeon determines the laser power to create a “barely visible” retinal burn at the margins of the
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selected grid pattern. If the surgeon has judged the test burn correctly, and the power is then decreased by 70%, the algorithm
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predicts that treatment should fall within the 0.010 watt-wide therapeutic window. (45, 46, 47, 88)
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To date, a single report of clinical EPM application has been published, in a small series of eyes with CSR. (45) No laserinduced retinal damage was noted; however, treatment results were modest; with a low rate of single treatment success, a high
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rate of recurrence and repeat treatment, and a high rate of treatment failure. (45) Because of the narrow TR of short-pulse CW
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laser, the risk of ineffective treatment is as high as inadvertent retinal burns. (45, 46, 47, 88)
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Although it has been suggested that PASCAL EPM can be used safely in the fovea, this remains to be demonstrated. (45) The EPM algorithm was developed in animal models with homogenous RPE melanin distribution. Human RPE melanin
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distribution, by contrast, is heterogeneous. (45, 46, 88) This heterogeneity may lead to variable laser uptake in patients at
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different retinal foci, as long experience with conventional photocoagulation attests. Reliance on subjective assessment of retinal
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test burns is inherently problematic. As LIRD may be invisible to the surgeon at the time of treatment, there is a real potential for
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visual loss due to inadvertent foveal injury if subjective assessment of laser intensity is in error. (54) Successfully hitting the
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narrow CW TR target to allow reliably safe CW treatment of the human fovea will likely require technology not yet available, such
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as accurate real-time RPE reflectometry.
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Most current commercial retinal laser manufactures now offer semi-automatic pattern scanning capabilities modeled on
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the PASCAL. While the PASCAL adheres to its original short-pulse CW format, other pattern scanning platforms offer
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conventional photocoagulation and / or micropulsed laser modes, including the NAVILAS, which has the capacity to be fully
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automatic. (15) While pattern scanning is aesthetically pleasing, the therapeutic benefit of various treatment patterns has not
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been established.
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Finally, several pattern scanning laser platforms also offer treatment mapping of the treatment location and document treatment parameters. This is designed to aid the surgeon considering re-treatment. Because retinal photocoagulation produces
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retinal damage easily seen by clinical exam or imaging postoperatively, the location of prior treatment is not generally in doubt.
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By the same token, local targeting is not a strategy of sublethal micropulse retinal laser treatment, which is currently applied in a
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“panmacular” fashion. (48, 50) Sublethal treatment can, by definition, be repeated as necessary without regard for the location of
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prior treatment. Thus, the clinical value of treatment mapping for retinal restorative treatment sublethal to the retina is unclear.
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certain costs. These include the cost of the technology itself, as well as the additional time required to select and program the
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desired mode of treatment for each patient. Particularly for performance of treatment sublethal to the retina, it is unclear whether
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these technologies offer actual advantages in treatment effectiveness and efficiency over an active joystick and foot on the
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repeat-mode pedal; however, in the search for further improvements in treatment efficacy, safety, and efficiency, further
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automation and improvements in retinal laser technology is a certainty.
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SELECTIVE RETINA THERAPY (SRT)
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The efficacy of conventional laser treatment for the treatment of DME was demonstrated by the ETDRS randomized clinical trial
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and the modified ETDRS study; (72) however, conventional laser treatment is associated with the destruction of full thickness
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retinal tissue and causes several side effects such as central scotomata, retinal hemorrhages, and choroidal neovascularization.
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Lesser power laser treatment for the macula was applied to avoid these complications of conventional laser in the modified
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ETDRS study. To further reduce retinal tissue damage, selective retina therapy (SRT) using microsecond pulses has been
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developed to obtain selective RPE damage while sparing adjacent photoreceptors or the choroid.
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Theory of SRT
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For the various retinal diseases associated with the dysfunction of the RPE, such as age-related macular degeneration (AMD),
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CSR, and DME, it might be sufficient to damage the RPE selectively without damaging the adjacent photoreceptors, the neural
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retina, and the choroid. The healing response to SRT has been called “retinal rejuvenation”. Just as with the PASCAL and nano-
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second (other short-pulse CW) lasers, it accomplished by cells adjacent to the LIRD expanding and sliding in to fill the laser
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defect. In mice proliferation RPE has been reported as part of the wound repair. This has not been observed in humans. (70)
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Although the precise mechanism of SRT is not fully understood, two theories can be considered to partially explain the unknown
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mechanism. One theory suggests that the beneficial effects of SRT are associated with the establishment of a new RPE cell
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barrier, with subsequent restoration of the RPE pump and barrier integrity. The other theory is that the bioactive substances such
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as matrix metalloproteinases (MMPs) and HSP 70 might play a role for therapeutic effect of SRT during healing process of RPE.,
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(9, 22, 72, 87, 89) Such theoretical considerations and the limitation of conventional laser treatment have led to the development
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of SRT laser treatments that selectively affect the RPE.
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The basis for selective RPE damage can be found in the light absorbing melanosomes within RPE cells that are influenced by
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certain wavelengths. About 50 % of laser with a green spectral range is absorbed in the RPE layer, and pulse energy is
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absorbed primarily by melanosomes within RPE cells. (47) In addition to wavelength, exposure time of pulse laser is an
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important parameter because the spatial extent of elevated temperature is reduced when multiple laser pulses of short duration
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are delivered. Thus, for achieving RPE selectivity, the effect of laser can be confined to the RPE cells by manipulating the pulse
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duration. The exposure time of each pulse is set in the microsecond range rather than of millisecond to prevent heat spread
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beyond the RPE, (~10um) sparing adjacent tissue structures. (10, 46) If the pulse energy is adequate, shorter than 5
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microseconds RPE cells are damaged by microvaporization around intracellular melanosomes. High peak temperatures that
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develop around melanosomes during micropulse laser irradiation create short-lived microbubbles that markedly increase the cell
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volume, leading to a mechanical disruption of RPE cells. (66) The SRT technique avoids the formation of macrobubbles that is
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associated with a risk of photodisruption of the retina or choroid. (23, 66, 76) Overall, SRT stimulates RPE cell expansion /
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migration into irradiated areas to improve metabolism at diseased sites without directly damaging adjacent retinal layers.
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Treatment endpoints of SRT
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Since SRT lesion is invisible on funduscopy, fundus fluorescein angiography (FFA) is the most reliable method to detect SRT
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lesions currently. Although SRT lesions showed transiently increased autofluorescence several days after SRT treatment, no
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instant change of SRT spot was observed on fundus autofluorecence in the previous studies. (78, 80, 81) Therefore, to confirm
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selective RPE damage quickly, two treatment endpoints including invisibility on fundoscopy and visibility on fluorescein
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angiography are used clinically. Two studies have demonstrated that FFA-positive SRT spots were faintly visible 1 week after
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SRT treatment and disappeared by 3 months. (20, 95) These clinical findings are consistent with the result of an in vivo animal
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experiment that SRT-treated defects were covered by intact bystander RPE cells within 7 days. (72, 73) The first SRT clinical trial
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using an Nd:YLF laser system and a pulse duration of 1.7 microseconds (100 pulses, at 100 and 500 Hz) revealed the potential
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effect of SRT in clinical use. (9) Subsequently, the SRT laser parameters were refined with even shorter pulses and fewer
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repetition rates. (23) Currently, SRT Laser system (R:GEN, Lutronic, Goyang-si, South Korea), Q-switched Nd:YLF laser: wave
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length; 527nm, micropulse duration; 1.7 µs, repetition rate; 100Hz, maximum number of micropulses in a burst:15) is used
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clinically. However, to find out the adequate therapeutic range of SRT treatment for individual patient, fluorescein angiography for
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test spots is mandatory before treatment spot irradiation.
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Real-time feedback-controlled dosimetry (RFD) during irradiation
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As with subthreshold micropulse laser (SDM), SRT does not cause visible changes in the retina, making it difficult to determine
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the adequate pulse energy of the laser. Even though pretreatment fluorescein angiography is useful method to detect RPE
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damages, it could be difficult for physician to monitor adequate RPE damage due to the wide range of inter or intrapersonal
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variation of retinal pigmentation. Therefore, to titrate the pulse energy in real-time without fluorescein angiography, optoacoustic
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(OA) and reflectometric (RM) methods for SRT have been developed. As transient microbubbles during SRT irradiation are
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responsible for the desired effects on RPE cells, it is useful to monitor microbubble development. (66) For detecting the
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appearance of microbubbles in real-time, OA and RM method detect feedback signals originating from microbubbles. Briefly, OA
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device detects the ultrasonic pressure as a form of optoacoustic feedback value (OAV) from microbubbles. (79, 80) RM device
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detects inflection of backscattered light as a form of optical feedback value (RV) from microbubbles. After each burst, based on
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the amplitude of feedback signals of each dosimetry, algorithm of dosimetry was optimized to obtain adequate RPE damages
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and to avoid both undertreatment (low OAV and RV due to no or tiny microbubbles) and overtreatment (high OAV and RV due to
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macrobubbles associated with burns). After evaluating the correlation between angiographic findings of SRT spots and the
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feedback signal form SRT spots, the sensitivity and specificity of OA dosimetry were 86% and 70% respectively and the
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sensitivity and specificity of RM dosimetry were 89% and 94% respectively. (79, 80) Although the accuracy of each dosimetry is
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already clinically applicable, the accuracy of dosimetry is expected to be improved by adopting two dosimetries simultaneously.
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Therefore, the real-time feedback-controlled dosimetry (RFD) implemented with both OA and RM method was developed.
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One of the major obstacles in SRT treatment is the risk of undertreatment when adequate pulse energy is chosen according to
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the angiographic finding from test spots, since there is a discrepancy in tissue structure of healthy test area and diseased
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treatment area. SRT with real-time feedback-controlled dosimetry algorithm (RFD-v1.0) using OA and RM devices provides OA
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feedback value and RAV value concurrently. One SRT spot consists of maximum of 15 micropulses (increment of 3.57% for the
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following micropulse). The first micropulse is set to be 50% of the last 15th micropulse. (Figure 8) When SRT irradiation reached
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the therapeutic threshold at which microbubbles occur in the RPE, adequately damaging the cells, the following micropulse is
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stopped automatically by RFD-v1.0. According to the algorithm that is designed to obtain the margin of safety, RFD gives three
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kinds of alarm signal based on the placement of automatic stop; automatic stops before 4th micropulse among 15 micropulses
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indicate an alarm for overtreatment, automatic stops after 12th micropulse indicate an alarm for undertreatment. Therefore, the
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physician can adjust the pulse energy based on these signals instantly to maintain the adequate pulse energy (automatic stops
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between 4th and 12th micropulse). (76)
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Clinical studies
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Diabetic macular edema
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Roider et al. reported that 33/39 eyes (84 %) with DME showed stable or improved visual acuity over a 6 month follow-up by
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using SRT treatment with OA method (81) (Similarly, in another uncontrolled prospective study, 16/23 eyes (70.%) of patients
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with DME showed improvement of more than one ETDRS line, and improvement of 1.7 dB in mean macular sensitivity was
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observed 6 months after SRT treatment with microperimetry. (69) In addition, retreatment with SRT also positively influenced a
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reduction of macular thickness 6 months after SRT. These clinical studies support for the safety and efficacy of SRT.
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Furthermore, the disappearance of SRT spot on FA at 3 months and the fading of transiently increased autofluorescence of SRT
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spot after SRT indicate the restoration of RPE monolayer. (69) Despite the differences of dosimetry and the baseline
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characteristics of the patients between two studies, SRT showed favorable results in these two prospective studies. The
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treatment strategy of SRT was to cover the edematous lesion with one-spot space between SRT spots rather than no-space to
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allow adjacent RPE cells for RPE healing. However, larger randomized clinical trials are needed to confirm the optimized density
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of spots and the efficacy of SRT treatment.
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Central Serous Chorioretinopathy
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Since dysfunction of RPE is one of important cause for development of subretinal fluid (SRF) in patients with CSR, SRT can be
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helpful to promote resolution of SRF by RPE rejuvenation. Klatt et al. reported that 71.4 % of 14 patients in SRT group showed a
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complete resolution of SRF compared to 40% of 16 patients of control group. (38) SRT was applied to cover all leaking points on
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fluorescein angiography for 12 eyes of 12 patients with chronic CSR 3 months after SRT. In this study, mean BCVA (logMAR)
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improved from 0.23 ± 0.12 at baseline to 0.14 ± 0.13 at 3 months. SRF completely resolved in 75% (9 eyes) at 3 months.
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Moreover, no scotomata were observed in the SRT-treated regions by microperimetry. However, under-treatment due to SRF
517
was suspected in some of treatment spots because of the decreased amplitude of feedback signals in this study. To decrease
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the risk of under-treatment, when the RFD provides an alarm signal based on the placement of automatic stop (from 12th and
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15th micropulse) the pulse energy can be increased by the operating surgeon instantly. (38) More recently, Yasui et al reported
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resolution of macular fluid present 3 months or more in 11/17 eyes with CSR. Visual acuity and microperimetry were improved,
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without treatment-associated scotomata. (95) (Figure 9)
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Drusen in Age Related Macular Degeneration
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As mentioned above, drusen reduction could be one of potential indication for SRT, in that LIRD is known to increase the release
524
of activated MMPs. (22, 98) Roider et al. reported that 3 of 10 patients with drusen showed disappearance of drusen 3 months
525
after SRT. (77) In another study, SRT was performed for soft drusen in two eyes. One eye did not change. In the other, there
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was some resolution of the drusen after 6 months (78) Conventional laser therapy for drusen is believed to have failed because,
527
although LIRD promoted disappearance of drusen, it also increased the risk of choroidal neovascularization. (90) This is may be
528
due to LIRD to Bruch membrane. Histologically, SRT has not produced breaks in Bruch membrane in previous studies; however,
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a study of SRT for age-related geographic atrophy (GA) in 6 eyes found that SRT accelerated the rate of GA progression by 50%
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compared to fellow eye controls. (77) This worsening was attributed to the LIRD produced by SRT, further emphasizing the risks
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of LIRD in dry AMD.
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Currently, SRT treatment requires fluorescein angiography for titration of pulse energy. Any discrepancy between the feedback signals from the test treatment areas require instant adjustment of the laser parameters to avoid under – or over-
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treatment, especially in the macula. SRT with RFD could assist titration of the pulse energy, by reducing reliance on subjective
535
observations of laser-induced retinal opacification. A clinical trial is planned to validate the safety and efficacy of SRT with RFD in
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the near future.
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NANOSECOND LASER
Effects of nanosecond laser treatment in animal models of disease
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Over the last 20 years research has focused on improving the selectivity of laser treatment to the RPE so as to reduce the level
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of collateral damage to the overlying retina that resulted from traditional continuous wave pulse lasers. (10, 23, 32, 49, 51, 59, 77,
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93) Pulsed lasers in the nanosecond range deliver a fraction of the energy of traditional continuous wave lasers, and provide a
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means for selectively targeting the RPE, whilst reducing damage to neighboring structures. (32) The selective effect of
546
nanosecond laser treatment on the RPE has been investigated in rodent and human retinas. (17, 34, 94) Notably, a single 3
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nanosecond laser pulse of 0.065mJ induced a lesion predominantly within the RPE that healed within 7 days. (34) During the
548
healing phase RPE cells immediately adjacent the laser-ablated area enlarge to re-epithelialize the lesion. In addition,
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proliferation of cultured human RPE cells has been demonstrated following nanosecond laser treatment with mouse RPE cells
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neighboring laser-ablated lesions immunoreactive for the cell cycle marker, cyclin D1. (17)
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The integrity of the retina overlying laser lesions induced by either a continuous wave laser suprathreshold or clinically-
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relevant nanosecond laser energy level has been investigated in rat, mouse and human retina. In contrast to treatment with a
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CW laser of the same wavelength (532nm), a nanosecond laser pulse set at a clinically appropriate laser energy (0.065mJ) was
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not associated with cell death in overlying photoreceptors in the mouse, nor disruption of Bruch membrane within the lasered
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region of a rat (energy setting 0.21mJ). (17, 34) These results have been confirmed in human retinae by immunocytochemical
556
analysis or SD-OCT imaging 5 days following laser treatment (90). In contrast, higher nanosecond laser energies were
557
associated with cell death of overlying photoreceptors, Müller cell gliosis, and an inflammatory reaction in rodent retina (17, 34,
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94). Retinal integrity was maintained after multiple treatments at the same anatomical site. These results highlight that treatment
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with a nanosecond laser pulse set at a clinically appropriate energy setting induces selective loss of the RPE without major
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effects on the overlying retinal neurons.
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The mechanism by which nanosecond laser treatment induces selective RPE cell loss is not well understood. It is well
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established that CW laser energy is absorbed by melanosomes within the RPE, causing thermal damage that diffuses into
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adjacent tissues. The Arrhenius law that describes the relationship between tissue temperature and damage is thought to hold
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for laser pulses down to the millisecond range; (16, 56) however, when laser pulses are of shorter duration the cellular effects
565
can no longer be attributed to thermal damage, but rather may involve thermomechanical effects. (80) It is currently thought that,
566
following exposure to a nanosecond laser pulse, approximately 50% of the laser energy is absorbed by melanin granules,
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causing a localized temperature rise around the melanin. Cell death occurs because of the formation of microbubbles that form
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around melanin granules that leads to cell expansion and rupture. (79)
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The major clinically relevant effects induced following nanosecond laser treatment include resolution of drusen in patients
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with intermediated age related macular degeneration and thinning of Bruch membrane in aged mice. (27, 34) Using ApoEnull
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mice, a mouse strain known to develop a thickened Bruch membrane, Jobling et al showed reduction in Bruch membrane
572
thickness three months after treatment with nanosecond laser. (93) In addition, a range of changes in gene expression within the
573
RPE were documented. In particular, nanosecond laser treatment was associated with a change in mRNA expression of a range
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of extracellular matrix genes that were consistent with the changes in Bruch membrane observed. Notably, expression of matrix
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metalloproteinases 2 and 3 as well as tissue inhibitors of matrix metalloproteinases (TIMP) were dysregulated in the RPE of
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lasered ApoEnull mice compared to unlasered age matched controls. Similarly, nanosecond laser treatment of cultured human
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RPE induced release of MMP2 and MMP9. (93)
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One of the more intriguing findings observed following treatment with a nanosecond laser are effects on the non-lasered
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fellow eye. In a subset of patients, nanosecond laser treatment was associated with a reduction in drusen in the fellow non-
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lasered eye. (27) In mice, similar changes in extracellular matrix gene expression occurred in both the lasered and non-lasered
581
fellow eye. Although the mechanism(s) by which the fellow non-lasered eyes are influenced by nanosecond laser remain unclear,
582
it is possible that early immune cell changes that occur within the first hour following treatment may play a role. (11) Indeed,
583
activated microglia have been shown previously to alter RPE gene expression and function. Further work is needed to further
584
explore the mechanisms underlying the effects of laser on the fellow eye, and its implications for clinical care of patients.
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In summary, the recent development of nanosecond lasers offers a means of selectively ablating the RPE, whilst sparing
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adjacent tissues. Recent animal studies suggest that treatment with a nanosecond laser induces a healing effect within the RPE
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that is associated with broad changes in the expression of extracellular matrix genes as well as thinning of Bruch’s membrane.
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Clinical studies
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The safety and efficacy of short-pulse, nanosecond (retinal rejuvenation therapy, 2RTTM) laser (Ellex Pty Ltd, Adelaide, Australia)
591
has been investigated in the treatment of DME and AMD (12, 27, 34, 73, 93) The 2RTTM laser is a 532 nm Q-switched YAG
592
laser. In these pilot studies, laser spots of 400 µm are delivered at short pulses of 3 nanoseconds to the macula, outside the
593
fovea. Subthreshold treatment energy for each individual is typically determined to be the energy level, one step lower than
594
visible retinal blanching, observed in a test spot placed outside the macular region.
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Diabetic Macular Edema
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To examine if nanosecond laser treatment was non-inferior to conventional laser treatment in DME, Casson et al.
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conducted a 6-month pilot trial involving 38 eyes. (12) Nanosecond laser treatment involved application of the laser spots in a
598
grid pattern to the thickened macular regions, with no direct treatment to microaneurysms. The treatment spots were 400µm
599
apart, and at least 500 µm from the fovea center, resulting in approximately 20 to 120 applications per eye. Conventional thermal
600
photocoagulation treatment involved targeting leaking microaneurysms with light burns of spot size of 100 um and duration of
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0.1s, and using the ETDRS direct/grid on only areas of thickened retina. Nanosecond laser and conventional laser resulted in
602
similar change in central macular thickness (CMT) and VA 6 months post-treatment. In this study, treatment randomization was
603
performed without blocking or stratification, resulting in a disproportionate gender representation in treatment groups. The
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treatment energy for the nanosecond laser was reported to be approximately 0.3 mJ; however, it is unclear the total energy that
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was used for treatment, including cases that was re-treated.
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Pelosini et al further investigated the efficacy of nanosecond laser treatment in 28 eyes with DME. (73) Nanosecond laser
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treatment was administered in a similar fashion to Casson and coworkers,, with areas of edema indicated by angiographic
608
images. The treatment energy level was set at 0.3 mJ. Visible retinal blanching observed with 0.6 mJ and variable degrees of
609
retinal reaction with 0.5 mJ. (12) The number of treatment shots ranged from 14 to 232. Re-treatment at 0.3 mJ was performed in
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14 eyes (50%) 4 months after initial laser. The loss of 10/28 eyes (36%) to follow up by 6 months resulted in different outcomes 3
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month versus 6 month post-initial laser and makes interpretation of the study results problematic. While improvement in VA was
612
not significant at 3 months, VA was significantly improved at 6 months. CMT was significantly reduced from baseline for the 3-
613
month cohort, but not for participants followed for 6 months. A moderate improvement in fixation stability and microperimetric
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retinal sensitivities was observed at 3 months. Subanalysis did not reveal differences due to gender. The absence of functional
615
loss as indicated by retinal sensitivity assessment and visual acuity suggested that photoreceptor damage was absent or
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minimal. In addition, the efficacy of nanosecond laser treatment was supported by the reduction or stability of CMT and
617
angiographic leakage at 6 months. A randomized controlled trial and a longer follow up period will provide further evidence of
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nanosecond laser as a safe and effective treatment for DME.
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Age Related Macular Degeneration
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Guymer et al applied 12 spots of 2RTTM nanosecond laser around the macula of one eye in 50 people with bilateral
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intermediate AMD with the aim of slowing the progression of the disease. (27) Treatment locations were initially 1500 um from
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the fovea center in a ring; however, after investigators noted a widespread effect on the clinical macular appearance, the protocol
623
was revised to require the treatment spots to be moved out to be just inside the superior and inferior arcades in an arc following
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the arcades. Treatment energy was set 20% lower than visible test spot energy. Following the use of 0.45 mJ in a test shot with
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a resultant dot hemorrhage in one eeye, the maximum energy was set at 0.3 mJ for subsequent treatments. Treatment energy
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ranged from 0.15 mJ to 0.45 mJ, with an average of 0.24 mJ. Nanosecond laser treatment did not improve VA in the treated eye
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at 12 months, while improvement in visual function was found in the worst point flicker sensitivity 1º from the fovea center of the
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treated eye at 12 months. Nanosecond laser treatment resulted in reduction (> 5% less from baseline) of drusen area in 44% of
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treated eyes at 12 months. Comparison with an historical control group (n= 116 eyes) revealed that this proportion was
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significantly greater than that observed in natural history. Drusen regression with one application of nanosecond laser treatment
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was maintained at 24 months, with 35% of treated eyes demonstrating this characteristic as compared to 11% in the natural
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history cohort. Of great interest, drusen regression was also observed in 22% of the fellow untreated eyes in the nanosecond
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laser-treated group at 12 months. Fundus autofluorescence (FAF) assessment of areas of drusen regression in a subgroup of
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nanosecond laser treated eyes at 12 and 24 months post-laser demonstrated stable FAF when compared to baseline in 9 of 12
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eyes. This allayed concerns of drusen regression from treatment leading to geographic atrophy (GA), as had been reported to be
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a natural sequel to drusen resolution in AMD. (96) Improvement in flicker threshold within the central 3° was observed in both the
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treated and untreated fellow eyes at 3 months post-laser. Of the 11 eyes presumed to be at greatest risk of progression (flicker
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defect > 15 dB), seven improved sufficiently to be taken out of this high-risk category. (Figure 10) The short follow up period in
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this study did not reveal if nanosecond laser treatment was effective in decreasing the number of cases that progressed to late
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AMD. The authors however cautioned against nanosecond laser treatment in patients with large (> 1000 µm) subfoveal
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drusenoid pigment epithelial detachments, as two participants with this feature lost vision over the follow up period from GA. The
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results of this study provided enough evidence to pursue nanosecond laser as a potential therapeutic intervention for AMD and a
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randomized controlled trial is currently being conducted to investigate if nanosecond laser can slow disease progression in
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intermediate AMD within 36 months (The LEAD study, clinicaltrials.gov: NCT01790802).
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CONCLUSION
The promise of laser retinal restoration therapy appears real and potentially important. Clinical observations and
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laboratory studies arising from the effectiveness of retina-sparing laser treatments have improved our understanding of the
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mechanism(s) of retinal laser therapy, replacing old concepts presuming the need for laser-induced retinal destruction, with
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laser-induced restoration of retinal and visual function. Recent reports of treatment applications beyond the conventional
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indications of DR and CSR may significantly expand future applications for retinal laser therapy. What remains is validation by
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larger, randomized trials. The weight and consistency of clinical and experimental data, and the convergence of thought we
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report, should increase the momentum for such studies.
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Method of Literature Search
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A systematic literature search of the Medline/PubMed database (www.ncbi.nlm.nih.gov/pubmed) was performed in December
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2016, using the following search parameters: Laser photocoagulation; subthreshold laser; micropulse laser; retinal laser;
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microsecond laser; panretinal photocoagulation; PASCAL; NAVILAS; Pattern Scanning Lasers; nanosecond laser; selective
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retina therapy; endpoint management; 2RT. Both English and non-English literature was included. The reference lists of the
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identified publications provided additional information and related sources. In keeping with the focus of this work, papers
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representing recent developmental milestones especially relevant to restorative retinal laser treatment, or new technological
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advances toward this end, were preferred for inclusion.
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The authors have no financial conflicts.
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Disclosures:
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44 JKL: Ojai Retinal Technologies, LLC, Ojai, California: Management, equity, patent.
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Retinal Protection Sciences, LLC, Ojai, California: Management, equity, patent.
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Ocular Proteomics, LLC, Towson, Maryland: Consultant
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Replenish, Inc, Pasadena, California: Equity, patent.
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ACCEPTED MANUSCRIPT 52 95 Yasui A, Yamamoto M, Hirayama K, Shiraki K, Theisen-Kunde D, Brinkmann R,Miura Y, Kohno T. Retinal sensitivity after selective retina therapy (SRT) on patients with central serous chorioretinopathy. Graefes Arch Clin Exp Ophthalmol.2017 Feb;255 (2):243-254.s
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Figure legends
Figure 1: Optical coherence tomography before (top); 3 months after (middle); and 6 months after (bottom) panmacular SDM laser for center-involving diabetic macular
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edema. Note reduction in macular thickening and resolution of macular exudates without laser-induced retinal damage. Snellen visual acuity 20/40 prior to treatment; and
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20/25 after treatment.
Figure 2: Late-phase intravenous fundus fluorescein angiographs of eye with severe non-proliferative diabetic retinopathy before (left) and 9 months after (right) a single treatment session of panmacular and panretinal SDM laser. Note regression of retinopathy, decrease micro-and macro vascular leakage, and capillary re-perfusion
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without laser-induced retinal damage. (Note: photographic timer is in error. Actual postinjection time for each photograph is approximately 10 minutes).
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Figure 3: Late-phase intravenous fundus fluorescein angiographs of eye with proliferative diabetic retinopathy before (left) and 5 months after (right) a single
treatment session of panretinal SDM laser. Note regression of neovascularization with decreased leakage of dye; reversal of background retinopathy severity; and absence of
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laser-induced retinal damage. (Note: Photographic timer is in error. Actual post-injection
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time for each photograph is approximately 10 minutes).
Figure 4: 10-minute post-injection intravenous fundus fluorescein angiographs of eye with proliferative diabetic retinopathy before (left) and 3 years after (right) a single treatment session of panretinal SDM laser. Note regression of neovascularization
severity.
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inferiorly, with decreased leakage of dye and reversal of background retinopathy
Figure 5: Omnifield threshold resolution (mesopic) perimetry visual field tests of the right
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eye of a patient with dry age-related macular degeneration, AREDS (Age Related Eye Disease Study) Category 3. The Omnifield measures the thresholds for best-corrected
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logMAR visual acuity under mesopic conditions at various intercepts throughout the central 200 of the visual field. A computer algorithm then uses these measurements to construct a false-color map (perimetry) of mesopic visual acuity thresholds through out the tested area. (A) Omnifield of right eye before; and (B) 3 months after SDM. Note improvements in all indices after SDM. BA6 = Best logMAR visual acuity (VA) within 60 of fixation; GMA = global macular acuity, or average logMAR VA in the central 200.
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Figure 6: Omnifield threshold resolution (mesopic) perimetry visual field tests of patient with advanced primary open angle glaucoma, before (left) and after (right) panmacular SDM laser. Note marked improvements after SDM laser. BA6 = Best logMAR visual
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acuity (VA) within 60 of fixation; GMA = global macular acuity, or average logMAR VA in central 200; VA=visual angle.
Figure 7: A 27-year old male with central serous chorioretinopathy showing retinal
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epithelium changes on color photograph (A) with juxtafoveal leak on fluorescein
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angiography (B and C). Spectral domain optical coherence tomography shows presence of subretinal fluid at baseline (D). Complete disappearance of subretinal fluid was noted after single session of navigated microsecond laser (E) at one month. Figure 8. The laser pulse energy is irradiated in a ramping manner (increment of 3.57%
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for the following micropulse) for every selective retina therapy (SRT) spot. Based on the algorithm of real-time feedback-controlled dosimetry (RFD-v1.0), if RFD detects the feedback signals from microbubbles at 7th micropulse, 8th micropulse wouldn’t be
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irradiated automatically.
Figure 9: A 45-year-old man presented with a 4-month history of subretinal fluid (SRF)
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in his right eye and diagnosed as central serous chorioretinopathy. Best-corrected visual acuity of right eye was 20/40. A. SRF on macular optical coherence tomography (OCT) was observed at initial presentation. B. SRF was completely resolved 1 month after receiving selective retina therapy (SRT) with real-time feedback-controlled dosimetry (RFD). C. Fluorescein angiography (FA) showed multiple focal leaking points at macular region. D. Initial fundus autofluorescence. E. There was no change on
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autofluorescence 1hr after SRT. F. Hyperfluorescence of SRT test spots (yellow box) was observed 3 hours after SRT. After ten SRT treatment spots (yellow arrowhead)
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were applied, multiple fluorescein leakages were also detected on FA. Figure 10: Color fundus images (A and B) and retinal pigment epithelium (RPE) layer maps from spectral domain optical coherence tomography (OCT) (cirrus) (C and D) of a
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patient with dry age related macular degeneration who underwent single laser session
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with 12 spots of 2RT laser (A and C are at baseline and B and D are 2 years post-laser)
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Table 1: Studies on use of subthreshold micropulse laser in Diabetic macular edema
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Results Compared conventional argon to micropulsed diode photocoagulation - VA remained stable in both groups throughout the follow-up period - Micropulsed diode gave significant reduction in retinal thickness in patients with focal macular edema - Laser-induced retinal damage (LIRD) noted -Eyes with residual DME treated with green mETDRS Luttrull et al Retrospective review of patients treated from 2000-2003 VA stable or improved in 85% (51) (2005) - Primary outcome measures: VA, FA leakage, and CSME - CSME decreased in 96% and resolved in 79% status - First without LIRD lesions. Undetectable - Follow-up: 3--29 months, mean 12.2 months ophthalmoscopically or angiographically - 5% DC throughout follow-up -810nm - Focal and diffuse DME -Fixed laser parameters used in all patients - Managed with SDM alone -First designed / intended to avoid LIRD -Pts treated between 2000-2003 -First to employ “low-intensity/high-density” “SDM” - Pre-OCT era technique Luttrull and Prospective follow up Overall reduction of macular thickness of 24% Spink -First report of OCT (time-domain) of subthreshold laser - 11 eyes with persistent or recurrent CSME (55) (2006) -15% DC were most improved (59% reduction of macular -810nm thickness) - High-density / low-intensity technique - Only report using 15% DC without LIRD -Fixed laser parameters used in all patients - OCT done at 1, 4, 12 weeks Sivaprasad et Non-comparative case-series - VA stable or improved in 84% in the first year, al (85) (2007) - 3-year follow-up maintained in the second year - Outcome measures: visual outcome and angiographic - By 3rd year, 92% maintained VA CSME status - More patients needed supplementary - 15% DC treatment in the 3rd year than in the 2nd year -810nm - CSME decreased in 92% and resolved in 88% in - Conventional (“low density”) grid technique the 1st year -Titrated laser parameters - 92% complete resolution by the 2nd year - By 3rd year; 28% had recurrent CSME - LIRD present Figueira et al Prospective randomized, controlled, double- masked trial No statistically significant difference in VA, (21) (2008) - Compared micropulsed diode/ argon green contrast sensitivity, and retinal thickness - 15% DC between the two groups -810nm - LIRD from MP - Conventional (“low density”) grid technique - Laser scarring much more apparent with argon -Titrated laser parameters laser compared to micropulsed diode (59% vs -LIRD considered prerequisite to effective treatment 13.9%)
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Study design Prospective, randomized trial - Follow-up: 5 months minimum - Main outcome measures: VA and macular thickness by OCT - First to report 5% duty cycle (DC) -810nm - Very long exposure duration (3.0 sec) - Conventional (“low density”) grid -LIRD considered prerequisite to effective therapy -Titrated laser parameters
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Authors/Year Laursen et al (43) (2004)
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- Outcome measures: VA, color fundus photographs, OCT, and contrast sensitivity - Follow-up: 12 months
Randomized controlled trial comparing SDM to mEDTRS
SDM superior to mETDRS
(91) (2010)
-MP fixed laser parameters used in all patients
-Both reduced central foveal thickness
-5% DC
-No LIRD with SDM by FAF
- Evaluated by microperimetry and FAF before / after
-LIRD with mEDTRS
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-Microperimetry worse after mETDRS; better after SDM
Randomized controlled masked single center clinical trial
(44) (2011)
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- New DME VA 20/40-20/400
-3 treatment arms: mETDRS; conventional (“lowdensity”) MP grid; high-density confluent MP -15% MP DC
High density MP grid superior to mETDRS -mEDTRS and conventional grid MP same reducing macular thickness -Conventional grid MP better VA than mEDTRS -High-density grid significantly better macular thickness reduction (avg 154um) and VA improvement (0.25 log MAR).
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-Titrated MP laser parameters
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-12 month follow up
-LIRD in all treatment arms
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- First report of SDM long-term safety -Compared LIRD risk of 5%, 10%, and 15% MP DC
Demonstrated high risk of LIRD if DC > 5% (p=0.0001) -All LIRD present at first follow up. No subsequent lesions -Computational tissue temp modeling corroborates clinical LIRD risk and efficacy findings
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Luttrull et al (56) Retrospective chart review eyes treated 2000-2010 (2012) - 212 eyes with DME and 40 with BRVO/ME
- Safety follow up: 3-120 months, median 47 months
- Reviewed 62 eyes evaluated before and after SDM with SD-OCT; median follow up 12 mos
- Computation tissue temperature modeling of MP laser parameters -
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- First reported case of transfoveal SDM for DME
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Review paper of MP in DME
Retrospective review of transfoveal SDM in patients with fovea-involving DME and pre-treatment VA 20/20-20/40
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-First series report of transfoveal laser for DME (single case reported by Luttrull and Dorin 2012) -810nm
-5% DC / SDM technique
-Fixed laser parameters used in all patients -Two treatment centers
- If presentation VA > 20/50, SDM used alone -If presentation VA < 20/40, combo therapy -No outcome difference between SDM mono vs. combo therapy
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-First report of MP (SDM) combination (anti-VEGF) therapy
-By SD-OCT, central foveal thickness (P=0.04) and maximum macular thickness (P<0.0001) improved
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-First report of Spectral domain OCT and FAF of subthreshold laser
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-Mechanisms of sublethal laser proposed -Subthreshold laser platforms compared -New sublethal laser applications predicted -Use of sublethal laser as preventive treatment in DR recommended
No adverse treatment effects -No LIRD -LogMAR VA and macular thickness by SD-OCT both significantly improved
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-39 eyes of 27 patients -20 eyes > 20/25 prior to treatment RCT single center comparative study of 577nm and 810nm MP for center-involving DME
(90) (2015)
577 and 810 both effective
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-No difference all outcome measures -SDM technique
-53 patients, 6 months follow up -Evaluated by SD-OCT, FAF, microperimetry Meta analysis of subthreshold diode micropulse laser vs. conventional photocoagulation for DME
Six RCTs were selected for this meta-analysis, including 398 eyes (203 eyes in the subthreshold MP laser group and 195 eyes in the conventional laser group).
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-No LIRD in either group -Fixed laser parameters used in all patients
(14) (2016)
Visual results of subthreshold MP superior to conventional laser
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Reduction in macular thickness by OCT same
Legend: VA = visual acuity; DC = duty cycle; LIRD = laser-induced retinal damage; ETDRS = Early Treatment of Diabetic Retinopathy Study; FA = fluorescein angiography; CSME = clinically significant macular edema; Pts = patients; SDM = low-intensity / high-density subthreshold diode micropulse laser; OCT = optical coherence tomography; MP = micropulse; FAF = fundus autofluorescence photography; mEDTRS = modified EDTRS; DME = diabetic macular edema; BRVO = branch retinal vein occlusion; mos = months; SD-OCT = spectral domain optical coherence tomography; combo = combination; DR = diabetic retinopathy; RTC = randomized clinical trial.
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Table 2: Studies on use of micropulse laser in proliferative diabetic retinopathy Study design - Prospective, interventional, non-comparable case-series - 13 patients with PDR - 39 patients with ME secondary to DR or BRVO - Patients with PDR had PRP and those with ME had grid laser photocoagulation - Clinical and angiographic assessment at 3 and 6 months -MP used to in high-duty cycle / high-intensity to create retinal burns -LIRD considered prerequisite for effective therapy
Results - 10/13 patients with PDR (77%) showed some regression of new vessels at 6 months - 22/39 patients with ME had resolution of DME at 6 months - In DME patients, the VA was maintained in 27 (69%) and improved in 11 (28%) - Extensive LIRD in all eyes
Desmettre et al (18) (2006)
- 6 patients with PDR or SNPDR -Prior to conventional continuous wave frequency doubled Nd:YAG (532 nm) PRP, repetitively pulse diode photocoagulation was performed in a small region of each patient’s superior retinal periphery. Six parallel rows of 10 diode laser burns were made. Each diode laser exposure was 125 mm in retinal diameter and 0.2 seconds in duration. Repetitively pulse diode photocoagulation was performed with 500 Hz, 0.3 ms micropulses (15% duty factor) in 0.2 second exposures. -The minimal power needed for visible continuous wave diode laser photocoagulation was determined from two adjacent rows of laser lesions. -The minimal power needed for visible diode micropulse photocoagulation was determined from four additional adjacent rows of laser lesions. -Red-free photographs and fluorescein angiograms were obtained immediately and 6 days after laser therapy to classify lesions as photographically or angiographically ‘‘visible’’ or ‘‘subvisible.’’ -LIRD considered prerequisite for effective therapy
-Visible diode laser lesions could be obtained in all patients with CW photocoagulation and 5 of 6 patients with micropulse treatment
- Retrospective chart review of 99 eyes of 69 patients undergoing MP laser PRP - Range of disease (from severe NPDR to severe PDR - Outcome measures: VA and end points (the occurrence of vitreous HGE or the need for vitrectomy) - Follow-up: mean 1 year (range 0.3--2.7 year). -Use of high-density treatment strategy -15% DC required due to larger peripheral spot and laser power limitations -Intent to avoid any LIRD
- Overall VA remained unchanged throughout follow-up and the proportion of eyes with excellent VA of 20/30 or better increased from 39% to 48% - Probability of treatment failure at 12 months: 12.5% for vitreous HGE and 14.6% for vitrectomy, comparable to conventional PRP. - No treatment complications observed - No LIRD detectable clinically or by FA - Minimal pre retinal fibrosis and membrane contraction. - Attributed to absence of clinical
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Authors/Year Moorman and Hamilton (62) (1999)
-The laser energy needed for visible CW and micropulse lesions was almost same.
Luttrull et al (52) (2008)
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- There was no significant difference in the power required to produce photographically and angiographically visible lesions.
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inflammation -No de novo DME or aggravation of existing DME -Reduced progression from SNDPR to PDR reduced from expected 50% to 7.9% (P=0.0001)
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Table 2 Legend: PDR=proliferative diabetic retinopathy. BRVO=branch retinal vein occlusion. DME=diabetic macular edema. DR=diabetic retinopathy. NPDR=non-proliferative diabetic retinopathy. SNPDR=severe non-proliferative diabetic retinopathy. MP=micropulse. PRP=panretinal photocoagulation. LIRD=laser-induced retinal damage. VA=visual acuity. Hz=Hertz. CW=continuous wave.
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