Retinal photocoagulation is effective, but it is also destructive. In the past, the prevailing view was that to be useful, laser therapy had to destroy oxygen-consuming rods and cones or retinal pigment epithelium (RPE) cells that produce angiogenic mediators. That perspective has been disproven now by numerous clinical trials and better understanding of the cellular and molecular changes induced by laser exposures.
PHOTOCOAGULATION'S BIOLOGICAL
EFFECTS
Photocoagulation upregulates inhibitors and downregulates
inducers of VEGF-related angiogenesis, as shown by
microarray and quantitative polymerase chain reaction
techniques.1-3 It downregulates matrix metalloproteinases,
which degrade extracellular matrix, and it upregulates
their tissue inhibitors, thereby inhibiting initiation and
maintenance of angiogenesis.4 It induces bone marrowderived
stem cells to migrate to exposure sites, where they
can differentiate into and replace dysfunctional or injured
cells.5-7 It also induces RPE apoptosis and choroidal heat
shock proteins.8,9 Additionally, it upregulates pigment
epithelium-derived factor (PEDF), a powerful inhibitor of
angiogenesis.10
MICROPULSE PHOTOCOAGULATION
Randomized prospective clinical trials demonstrate that
subthreshold micropulse photocoagulation is as effective
a treatment for diabetic macular edema as conventional,
more damaging laser therapy.11,12 Moreover, a recent study
documents that it can improve visual sensitivity, whereas
standard suprathreshold ETDRS-type photocoagulation
decreases sensitivity.13
The bottom line is that subthreshold micropulse photocoagulation can be constructive without being destructive, whereas conventional suprathreshold photocoagulation causes permanent rod, cone, and retinal ganglion photoreceptor damage, with corresponding losses in scotopic, mesopic, and circadian photoreception.17,20
Micropulse photocoagulation can decrease retinal damage by: 1) using subvisible or barely visible treatment endpoints; 2) localizing laser effects with exposures 100 times shorter than those available with manual or automatedpattern conventional photocoagulators; and 3) optimizing laser wavelength.14
SUBTHRESHOLD ENDPOINTS
Photocoagulation occurs when laser radiation is
absorbed primarily by melanin in the RPE and the
choroid.14-17 Light absorption in pigmented tissues converts
laser energy into heat, increasing the temperature of
the pigmented tissue targets. Heat conduction then
spreads this temperature rise from laser-irradiated pigmented
tissue to overlying neural or collateral retina.
Overlying retina damaged by heat conduction loses its
transparency and scatters white slit lamp light back at the
observer. Retinal whitening is the optical signature of a
chorioretinal burn. More damage means less transparency
and a whiter lesion.14,17
There are many “thresholds” for retinal laser exposures. Hemorrhages occur at roughly three times the exposure needed to produce ophthalmoscopically apparent lesions. Invisible lesions that are angiographically apparent occur at approximately half the laser exposure needed for a visible lesion. Maximum permissible exposure (MPE) levels established by international laser safety standards represent roughly one-tenth the laser exposure needed to produce a retinal effect.14,17,18
In clinical terms, “subthreshold” means “invisible.” Smaller retinal irradiances (power density in W/cm2) produce therapeutic effects with lower retinal temperature rises that cause less or no retinal damage.14,17
LOCALIZING RETINAL EFFECTS
Figure 1 shows retinal temperature increase in the neural
retina, the RPE, and the choroid for a 200-micron diameter
retina spot, and laser exposures ranging in duration from
1 microsecond to 0.1 second.15,16 For very short microsecond
exposures, retinal temperature increases only in the
RPE and choroid, where light is directly absorbed. For
lengthier exposures, heat conduction spreads temperature
elevations to the neural retina that are comparable to
those in the RPE and choroid. Thus, neural retinal damage
is caused primarily by heat conduction, and shortening a
laser pulse can localize its chorioretinal effects.14-17
To confine laser effects to RPE cells, which are only 10 to 14 microns tall, laser exposures must be less than approximately 0.7 msec in duration, which is roughly 50 times shorter than the shortest exposures available with manual or automated-pattern conventional photocoagulators. Additionally, delivery of the full laser energy dose in a single 0.7 msec pulse can cause hemorrhage and postoperative choroidal neovascularization, which is one of the reasons ruby lasers were abandoned early in the evolution of clinical photocoagulators.14
Micropulse photocoagulation provides an effective workaround for this problem. Laser energy is delivered in a burst (“envelope”) of micropulses, rather than a single pulse. There is insufficient time for heat conduction to spread temperature rise to adjacent sites, each micropulse denatures only a small fraction of target tissue molecules, and repetitive micropulses combine to produce therapeutic effects.14
OPTIMIZING LASER WAVELENGTH
Another way to localize damage with micropulse photocoagulation
is by optimizing laser wavelength.17 Over
the years, numerous laser wavelengths have been used for
retinal photocoagulation and laser trabeculoplasty.
Melanin is the most effective chorioretinal absorber. Its
absorption decreases with increasing wavelength, as does
that of deoxyhemoglobin and oxyhemoglobin, as shown
in Figure 2. Figure 2 also shows that oxyhemoglobin has
an absorption peak at 577 nm in the yellow part of the
visible spectrum.14,17
Red and infrared laser light cause deeper, less visible, and often more painful lesions.17 Conversely, deeper lesions may reduce damage to retinal ganglion photoreceptors. 19,20 A common misperception is that red light is particularly useful for laser photocoagulation when there is hazy media or vitreous hemorrhage. The fact is the retina is visualized with white slit lamp light, not with red laser light. Treatment in hazy media is limited by visualizing retinal targets with white slit lamp light, not by difficulty getting a laser beam to a visible target.14,17
No controlled trial has proven the clinical advantage of one laser wavelength over another in standard grossly suprathreshold retinal photocoagulation, but dye lasers exploited the 577 nm yellow peak of oxyhemoglobin to improve the comfort and convenience of standard clinical retinal photocoagulation.14,17 The 577 nm yellow laser light provided excellent lesion visibility, low intraocular light scattering and pain, negligible xanthophyll absorption, and high choriocapillaris absorption for more uniform effects in patients with light or irregular fundus pigmentation.17 In fact, there is about a 15% reduction in the variability in laser light absorption with 577 nm yellow light as compared with 532 nm green light.
Two things happened when dye laser photocoagulators were introduced in the mid-1980s. First, they quickly became popular with retina specialists. Second, although clinicians could select green, yellow, and red light, many decided rapidly to leave the photocoagulator set at 577 nm yellow light. Dye lasers went away in the 1990s because they were costly, complex, difficult to maintain, and simply not economically justifiable. Since then, 561 nm green light has been marketed as an alternative “yellow” light, but 561 nm light is not yellow.21 Furthermore, it is not an optimal clinical wavelength because it has higher absorption in deoxyhemoglobin than oxyhemoglobin and lower absorption in oxyhemoglobin than either standard 532 nm green or 577 nm yellow light.14,17
LASER MULTIFUNCTIONALITY
It has taken two decades for laser technology to catch
up with clinical demands, but new semiconductor laser
devices now provide cost-effective, reliable, solid-state 577 nm yellow laser light for clinical use, exploiting the
same 577 nm yellow peak in the absorption spectrum of
oxyhemoglobin that dye laser users found so effective.
The IQ 577 photocoagulator (Iridex Corporation,
Mountain View, CA) uses this new technology to provide
two watts of 577 nm yellow laser light for optimized
wavelength for: 1) standard retinal photocoagulation; 2)
MicroPulse retinal photocoagulation; 3) standard laser
trabeculoplasty, and; 4) MicroPulse laser trabeculoplasty.
Despite pharmacological advances, laser photocoagulation remains a critical part of modern retina and glaucoma practice. Clinical instrumentation and methods are available for minimizing collateral retinal laser damage and increasing postoperative visual sensitivity. Opticallypumped semiconductor technology now provides 577 nm yellow laser light optimized for conventional and micropulse photocoagulation.
Martin A. Mainster, PhD, MD, FRCOphth, is the Luther and Ardis Fry Professor Emeritus of Ophthalmology of the University of Kansas School of Medicine. He is a consultant for Abbott Medical Optics, Iridex, and Ocular Instruments. He does not have a proprietary interest in any product, manufacturer or patent.
_1773249222.png?auto=compress,format&w=75)
