New
Frontiers in Selective Retinal Lasers
Yannis
Mantas Paulus
Yannis Mantas Paulus, Johns Hopkins University, Wilmer Eye
Institute, 600 North Wolfe Street, Woods 272, Baltimore, MD 21287, USA
Correspondence to: Yannis Mantas Paulus, MD, Johns Hopkins
University, Wilmer Eye Institute, 600 North Wolfe Street, Woods 272, Baltimore,
MD 21287, USA
Email: Yannis.paulus@gmail.com
Telephone: +1-410-707-7018
Received: March 10,
2015
Revised: March 28, 2015
Accepted: March 31, 2015
Published online: June 1, 2015
ABSTRACT
Retinal laser
therapy remains the treatment of choice for proliferative diabetic retinopathy,
retinal vascular diseases, and retinal tears. Advances in laser technology have
created new treatments that minimize collateral tissue damage while retaining
the therapeutic effects of laser therapy. Recent innovations in retinal laser
therapy are reviewed, including selective millisecond pulse duration laser,
reduced intensity laser therapy, micropulse laser, and selective retinal therapy.
These innovations have demonstrated promise in small clinical trials.
© 2015 ACT. All
rights reserved.
Key words: Laser; Selective retinal therapy; Micropulse laser;
Microsecond laser; Retinal wound healing; Photocoagulation
Paulus YM. New Frontiers
in Selective Retinal Lasers. International
Journal of Ophthalmic Research 2015; 1(1): 1-4 Available from: URL:
http://www.ghrnet.org/index.php/ijor/article/view/1103
INTRODUCTION
Retinal laser photocoagulation was first described over 50 years ago and
remains the standard of care for many retinal diseases[1,2]. Conventional retinal laser
photocoagulation for diabetic retinopathy, retinal vascular diseases, and
retinal tears is typically performed with a continuous wave laser in the green,
yellow, or red range, primarily at 514 or 532 nanometers (nm), pulse duration
of 100 to 200 milliseconds (ms), spot size from 100 to 500 micrometers (um),
and laser power to achieve the clinical endpoint, typically around 100 to 750
milliwatts (mW). Laser therapy is typically empirically titrated to a visible
clinical effect of greyish whitening of the retina, which corresponds to
photoreceptors necrosis and inner retinal damage.
Although it
has proven to be effective clinically[3-5], adjacent retina is
damaged with the laser application, resulting in retinal atrophy and thinning
in the regions of laser application, scotomas[6,7], post-laser
lesion enlargement[8,9], subretinal and choroidal neovascularization[10],
subretinal fibrosis[11], and progressive visual field loss[12,13].
These adverse effects of laser can significantly impact a patient’s quality of
life. These concerns on the destructiveness of laser therapy have led to
numerous investigations to provide the same therapeutic effect of lasers with
minimizing the side-effect profile, including modulations in pulse duration in
the millisecond and microsecond domain, lesion intensity, multiple pulses to
allow thermal relaxation, and axial lesion localization, which are discussed
below along with clinical results.
Increasing
Selectivity of Millisecond Pulse Duration Laser
Investigations have been performed using shorter millisecond pulse
duration laser ranging from 1 to 100 milliseconds compared to conventional
laser[14]. Shorter millisecond pulse durations resulted in decreased
lesion size for an equivalent clinical appearance of the lesion and improved
lesion localization but reduced safety window to rupture Bruch's membrane. A
pulse duration of 20 ms was found to adequately balance safety with speed.
Further modifications have been proposed, including spatial and temporal
modulation of laser beams[15], pattern scanning retinal
photocoagulation[16], and reduced lesion intensity (Figure 1)[17,18].
Modifications
have also been described using OCT to guide more selective focal laser
treatment. OCT guided focal laser resulted in 2.5 letters of improved vision (p=0.04)
and a 45.56 micron reduction in central subfield thickness (p<0.001)
compared to conventional modified Early Treatment Diabetic Retinopathy Study
(mETDRS) focal laser at 1 year[19]. Further modifications have been
described using laser dosimetry to empirically titrate to barely visible burns.
The power is reduced from this level and has been shown to result in invisible
burns funduscopically but visible on FA and OCT at 50-75% of barely visible
level and invisible burns at 30-50% of barely visible level using a software
termed Endpoint Management[20].A small clinical study of 16 patients
with chronic central serous chorioretinopathy of over 4 months duration using
30% of barely visible pulse energy found a gain of 12 letters of vision by 2
months (p<0.001) with a decrease in central macular thickness from
350 to 282 (p=0.004)[21]. Subvisible laser burns have been
shown to result in upregulation of inflammatory markers after laser application[22]
and improved response to oxidative stress[23]. The reduced intensity
and pulse duration laser has been shown in rabbits to result in retinal lesions
in which the photoreceptors fill-in the laser spot within four months (Figure
2)[24]. This has been shown to result in both restoration of retina
structure and function in these laser spots with intact retinal ganglion cells
in the laser region through retinal remodeling[25]. This restoration
of morphology has also been shown in humans with OCT following less intense
laser burns[26,27].
Micropulse
Laser
In contrast to the long exposures and large spots used in TTT, shorter
bursts of NIR radiation (810 nm) with small spot sizes (100 to 200 µm) have
also been applied for non-damaging retinal phototherapy, termed subvisible
diode micropulse (SDM) laser therapy. In this technique, treatment of retinal
vascular disease is performed with the express goal of avoiding cellular
destruction. Mathematical models of SDM have demonstrated that the hyperthermia
in this approach does not exceed the threshold of cell toxicity and has a high
degree of selectivity. Low-intensity/high-density SDM allows for complete and
confluent (high-density) coverage of the entire diseased retina, such as the
areas of macular thickening constituting diabetic macular edema (DME) or
ischemic retina with proliferative diabetic retinopathy (PDR). Subthreshold
micropulse laser delivers a series of short pulses to allow thermal dissipation
between each pulse[28]. Subthreshold laser has been shown in
pathologic and histochemical analyses to reduce the changes to the surrounding
choroidal and retinal cells[29].
The micropulse
810 nm diode, low-intensity/high-density subvisible photocoagulator has also
been shown to be clinically effective in the treatment of DME and PDR in small
clinical series. SDM has been shown to be as effective as modified Early
Treatment Diabetic Retinopathy Study (mETDRS) focal laser in the treatment of
clinically significant DME. SDM results in improved clinical examination and
retinal thickness measurement with optical coherence tomography (OCT) without
producing visible retinal damage[30]. Beneficial effects in the
treatment of retinal neovascularization from PDR have also been reported[31].
These studies, however, are limited by their size and the duration of patient
follow-up[32].
Selective
Retinal Therapy with Microsecond Pulse Duration Laser
One method to provide retinal phototherapy without severe permanent
damage is selective treatment of the retinal pigment epithelium (RPE) by
decreasing the laser pulse duration, termed selective retinal therapy (SRT). It
has been demonstrated that microsecond (µs) pulse durations that are absorbed
by melanin can selectively destroy RPE without damaging the retina[33,34].
Due to minimal thermal heat diffusion, microsecond and nanosecond laser pulses
can produce explosive vaporization of melanosomes, resulting in selective
damage to the RPE layer while sparing the photoreceptors and the inner retina.
Subsequent RPE proliferation and migration restores RPE continuity. SRT has
also been shown to cause a release of inflammatory markers, including matrix
metalloproteinases 2 and 9, which may play a role in its treatment efficacy[35].
Multifocal ERG and histology following SRT has been shown to result in no
significant retinal change 30 days after SRT laser application[36].
The first
RPE-selective retinal laser treatment was achieved using 5 µs argon laser
pulses at 514 nm and a repetition rate of 500 Hz[37].Currently,
several microsecond-pulsed laser systems are available[38,39].
Recently, an alternative SRT approach has been developed based on a rapidly
scanning continuous wave laser, such that RPE cells are exposed to a scanning
laser light to achieve dwell times of a few microseconds[40,41].
This technique has been further refined using an automatic, energy ramping, non-contact,
reflectometric dosimetry technique[42].
Several small
clinical studies have demonstrated the efficacy of SRT in diabetic retinopathy,
diabetic macular edema, central serous chorioretinopathy, and subfoveal fluid
after a rhegmatogenous retinal detachment[43-46]. A randomized
prospective study of 30 patients with chronic central serous chorioretinopathy
of at least 3 months' duration with 14 eyes randomized to SRT and 16 eyes as
controls found a statistically significant improvement in mean visual acuity
with 12.7 letters gained in the laser group versus 6.3 letters gained in the
control group (p=0.04). SRT also resulted in less subretinal fluid with
a decrease of 203 microns in retinal thickness with laser versus 41 microns in
control patients at 3 months (p=0.005)[47]. A prospective
uncontrolled study of 39 patients with diabetic macular edema found an
improvement of 2.4 letters of vision 6 months after laser application (p=0.02).
84% of eyes either had stable or improved vision and there were no adverse
events associated with SRT[48].
Future
Horizons
Advances in laser technology have created new treatments that minimize
collateral tissue damage while retaining the therapeutic effects of laser
therapy. Thermal damage with conventional laser limits its utility in treating
the macula due to tissue damage and scarring. Recently developed improvements
minimize or eliminate this side effect. Studies have indicated that laser power
approximately half that of barely visible burns produces cellular changes while
minimizing tissue injury[49]. This allows the physician to elicit a
therapeutic biological response without causing permanent cell death. Further
studies are needed to elucidate the mechanism of cellular response leading to
clinical efficacy of laser therapy.
To prove the
clinical utility of these new modalities, larger randomized control clinical
trials with longer follow-up are required to ensure that these meet or exceed
the current clinical standard of care. More clinical trials are also needed of
laser treatment in combination with pharmacologic therapy, such as concomitant
laser and anti-vascular endothelial growth factor (VEGF) or steroid therapy. We
stand on the cusp of a transformation in our care of patients through the use
of personalized, targeted therapy and novel laser treatments promise to play an
important role in retinal conditions.
CONFLICT OF INTERESTS
The author has no conflicts of interest to declare.
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Peer reviewer: Carolina Arruabarrena,
MD, Retina Unit, Universitary Hospital Príncipe de Asturias, Carretera a Meco
s/n, Alcalá de Henares, 28805, Spain.
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