Note: Descriptions are shown in the official language in which they were submitted.
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SUBTHRESHOLD MICROPULSE LASER PROPHYLACTIC TREATMENT FOR CHRONIC
PROGRESSIVE RETINAL DISEASES
BACKGROUND OF THE INVENTION
[Para 1] The present invention generally relates to phototherapy or
photostimulation of biological tissue, such as laser retinal photocoagulation
therapy. More particularly, the present invention is directed to a process for
treating an eye to stop or delay the onset of symptoms of retinal diseases in
a
patient using harmless, subthreshold phototherapy or photostimulation of the
retina.
[Para 2] The complications of chronic progressive retinal diseases, such as
diabetic retinopathy (DR) and age-related macular degeneration (AMD)
constitute major causes of visual loss worldwide. Complications of diabetic
retinopathy remain a leading cause of vision loss in people under sixty years
of
age. Diabetic macular edema is the most common cause of legal blindness in
this patient group. Diabetes mellitus, the cause of diabetic retinopathy, and
thus diabetic macular edema, is increasing in incidence and prevalence
worldwide, becoming epidemic not only in the developed world, but in the
developing world as well. Diabetic retinopathy may begin to appear in persons
with Type I (insulin-dependent) diabetes within three to five years of disease
onset. The prevalence of diabetic retinopathy increases with duration of
disease. By ten years, 14%-25% of patients will have diabetic macular edema.
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By twenty years, nearly 100% will have some degree of diabetic retinopathy.
Untreated, patients with clinically significant diabetic macular edema have a
32% three-year risk of potentially disabling moderate visual loss.
[Para 3] General laser treatment of the retina for various disorders has been
employed for over fifty years. Traditionally, laser photocoagulation
characterized by intentional laser-induced thermal destruction and
scarification
of the retina has been employed. Photocoagulation has been found to be an
effective means of producing retinal scars, and has become the technical
standard for macular photocoagulation for diabetic macular edema. Due to the
clinical effectiveness of retinal laser photocoagulation, the long-held view
in
medicine was that the beneficial effects of treatment were due to the retinal
damage created by photocoagulation.
[Para 4] There are different exposure thresholds for retinal lesions that are
haemorrhagic, ophthalmoscopically apparent, or angiographically
demonstrable. A "threshold" lesion is one that is barely visible
ophthalmoscopically at treatment time, a "subthreshold" lesion is one that is
not visible at treatment time, and "suprathreshold" laser therapy is retinal
photocoagulation performed to a readily visible endpoint. Traditional retinal
photocoagulation treatment requires a visible endpoint either to produce a
"threshold" lesion or a "suprathreshold" lesion so as to be readily visible
and
tracked. In fact, it has been believed that actual tissue damage and scarring
are
necessary in order to create the benefits of the procedure. The gray to white
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retinal burns testify to the thermal retinal destruction inherent in
conventional
threshold and suprathreshold photocoagulation.
[Para 5] With reference now to FIG. 1, a diagrammatic view of an eye,
generally
referred to by the reference number 10, is shown. When using phototherapy,
the laser light is passed through the patient's cornea 12, pupil 14, and lens
16
and directed onto the retina 18. The retina 18 is a thin tissue layer which
captures light and transforms it into the electrical signals for the brain. It
has
many blood vessels, such as those referred to by reference number 20, to
nourish it. Various retinal diseases and disorders, and particularly vascular
retinal diseases such as diabetic retinopathy, are treated using conventional
thermal retinal photocoagulation, as discussed above. The fovea/macula
region, referred to by the reference number 22 in FIG. 1, is a portion of the
eye
used for color vision and fine detail vision. The fovea is at the center of
the
macula, where the concentration of the cells needed for central vision is the
highest. Although it is this area where diseases such as age-related macular
degeneration are so damaging, this is the area where conventional
photocoagulation phototherapy cannot be used as damaging the cells in the
foveal area can significantly damage the patient's vision. Thus, with current
convention photocoagulation therapies, the foveal region is avoided.
[Para 6] Until the advent of thermal retinal photocoagulation, there was
generally no effective treatment for diabetic retinopathy. Using
photocoagulation to produce photothermal retinal burns as a therapeutic
maneuver was prompted by the observation that the complications of diabetic
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retinopathy were often less severe in eyes with preexisting retinal scarring
from
other causes. The Early Treatment of Diabetic Retinopathy Study demonstrated
the efficacy of argon laser macular photocoagulation in the treatment of
diabetic macular edema. Full-thickness retinal laser burns in the areas of
retinal pathology were created, visible at the time of treatment as white or
gray
retinal lesions ("suprathreshold" retinal photocoagulation). With time, these
lesions developed into focal areas of chorioretinal scarring and progressive
atrophy.
[Para 7] With visible endpoint photocoagulation, laser light absorption heats
pigmented tissues at the laser site. Heat conduction spreads this temperature
increase from the retinal pigment epithelium and choroid to overlying non-
pigmented and adjacent unexposed tissues. Laser lesions become visible
immediately when damaged neural retina overlying the laser sight loses its
transparency and scatters white ophthalmoscopic light back towards the
observer.
[Para 8] Conventional thinking assumes that the physician must
intentionally create retinal damage as a prerequisite to therapeutically
effective
treatment. With reference to FIG. 2, FIGS. 2A-2F are graphic representations
of
the effective surface area of various modes of retinal laser treatment for
retinal
vascular disease. The gray background represents the retina 30 which is
unaffected by the laser treatment. The black areas 32 are areas of the retina
which are destroyed by conventional laser techniques. The lighter gray or
white
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areas 34 represent the areas of the retina affected by the laser, but not
destroyed.
[Para 9] FIG. 2A illustrates the therapeutic effect of conventional argon
laser
retinal photocoagulation. The therapeutic effects attributed to laser-induced
thermal retinal destruction include reduced metabolic demand, debulking of
diseased retina, increased intraocular oxygen tension and ultra production of
vasoactive cytokines, including vascular endothelial growth factor (VEGF).
[Para 10] With reference to FIG. 2B, increasing the burn intensity of the
traditional laser burn is shown. It will be seen that the burned and damaged
tissue area 32 is larger, which has resulted in a larger "halo effect" of
heated,
but undamaged, surrounding tissue 34. Laboratory studies have shown that
increased burn intensity is associated with an enhanced therapeutic effect,
but
hampered by increased loss of functional retina inflammation. However, with
reference to FIG. 2C, when the intensity of the conventional argon laser
photocoagulation is reduced, the area of the retina 34 affected by the laser
but
not destroyed is also reduced, which may explain the inferior clinical results
from lower-intensity/lower-density or "mild" argon laser grid photocoagulation
compared to higher-intensity/higher-density treatment, as illustrated in FIG.
2B.
[Para 1 1 ] With reference to FIG. 2D, it has been found that low-fluence
photocoagulation with short-pulse continuous wave laser photocoagulation,
also known as selective retinal therapy, produces minimal optical and lateral
spread of laser photothermal tissue effects, to the extent that the area of
the
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retina affected by the laser but not destroyed is minimal to nonexistent.
Thus,
despite complete oblation of the directly treated retina 30, the rim of the
therapeutically affected and surviving tissue is scant or absent. This
explains
the recent reports finding superiority of conventional argon laser
photocoagulation over PASCAL for diabetic retinopathy.
[Para 1 2] That iatrogenic retinal damage is necessary for effective laser
treatment of retinal vascular disease has been universally accepted for almost
five decades, and remains the prevailing notion. Although providing a clear
advantage compared to no treatment, current retinal photocoagulation
treatments, which produce visible gray to white retinal burns and scarring,
have
disadvantages and drawbacks. Conventional photocoagulation is often painful.
Local anesthesia, with its own attendant risks, may be required.
Alternatively,
treatment may be divided into stages over an extended period of time to
minimize treatment pain and post-operative inflammation. Transient reduction
in visual acuity is common following conventional photocoagulation.
[Para 1 3] In fact, thermal tissue damage may be the sole source of the
many
potential complications of conventional photocoagulation which may lead to
immediate and late visual loss. Such complications include inadvertent foveal
burns, pre- and sub-retinal fibrosis, choroidal neovascularization, and
progressive expansion of laser scars. Inflammation resulting from the tissue
destruction may cause or exacerbate macular edema, induced precipitous
contraction of fibrovascular proliferation with retinal detachment and
vitreous
hemorrhage, and cause uveitis, serous choroidal detachment, angle closure or
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hypotony. Some of these complications are rare, while others, including
treatment pain, progressive scar expansion, visual field loss, transient
visual
loss and decreased night vision are so common as to be accepted as inevitable
side-effects of conventional laser retinal photocoagulation. In fact, due to
the
retinal damage inherent in conventional photocoagulation treatment, it has
been limited in density and in proximity to the fovea, where the most visually
disabling diabetic macular edema occurs.
[Para 1 4] Notwithstanding the risks and drawbacks, retinal
photocoagulation
treatment, typically using a visible laser light, is the current standard of
care for
proliferative diabetic retinopathy, as well as other retinopathy and retinal
diseases, including diabetic macular edema and retinal venous occlusive
diseases which also respond well to retinal photocoagulation treatment. In
fact,
retinal photocoagulation is the current standard of care for many retinal
diseases, including diabetic retinopathy.
[Para 1 5] Currently, retinal imaging and visual acuity testing guide
management of the detected retinal diseases. As end-organ structural damage
and vision loss are late disease manifestations, treatment instituted at this
point must be intensive, often prolonged and expensive, frequently failing to
improve visual acuity, and rarely restoring normal vision.
[Para 1 6] Another problem is that the treatment requires the application
of a
large number of laser doses to the retina, which can be tedious and time-
consuming. Typically, such treatments call for the application of each dose in
the form of a laser beam spot applied to the target tissue for a predetermined
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amount of time, from a few hundred milliseconds to several seconds. Typically,
the laser spots range from 50-500 microns in diameter. Their laser wavelength
may be green, yellow, red or even infrared. It is not uncommon for hundreds or
even in excess of one thousand laser spots to be necessary in order to fully
treat the retina. The physician is responsible for insuring that each laser
beam
spot is properly positioned away from sensitive areas of the eye, such as the
fovea, that could result in permanent damage. Laying down a uniform pattern
is difficult and the pattern is typically more random than geometric in
distribution. Point-by-point treatment of a large number of locations tends to
be a lengthy procedure, which frequently results in physician fatigue and
patient discomfort.
[Para 17] Accordingly, there is a continuing need for a process for
treating an
eye to stop or delay the onset or symptoms of retinal diseases in a patient
without many of the drawbacks and complications resulting from conventional
photocoagulation treatments. There is also a continuing need for a process for
such treatment before retinal imaging abnormalities are detectable.
Furthermore, there is a continuing need for a process that provides the
application of a large number of laser doses to the treatment area, or even
the
entire retina, in a simultaneous manner without damaging the retinal tissue.
The present invention fulfills these needs, and provides other related
advantages.
Heading
SUMMARY OF THE INVENTION
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[Para 18] The present invention is directed to a process for treating an
eye to
stop or delay the onset or symptoms of retinal diseases in a patient. The
process generally comprises the steps of determining that an eye has a risk
for
a retinal disease before detectable retinal imaging abnormalities. A laser
light
beam is generated that creates sublethal, true subthreshold photocoagulation
in retinal tissue that provides preventative and protective treatment of the
retinal tissue of the eye.
[Para 19] The treated retina may comprise the fovea, foveola, retinal
pigment
epithelium, choroid, choroidal neovascular membrane, subretinal fluid, macula,
macular edema, parafovea, and/or perifovea. The laser light beam may be
exposed to substantially the entire retina and fovea.
[Para 20] Determining that an eye of the patient has a risk for a retinal
disease before detectable retinal imaging abnormalities may include the step
of
ascertaining that the patient is at risk for a chronic progressive
retinopathy,
including diabetes, a risk for age-related macular degeneration or retinitis
pigmentosa, or results of a retinal examination or retinal test of the patient
is
abnormal. A test may be conducted to establish that the patient has a risk for
a
retinal disease. The test may comprise a retinal physiology test or a genetic
test.
[Para 21] The laser light beam may be generated as a subthreshold sublethal
micropulse laser light beam having a wavelength greater than 532nm and a
duty cycle of less than 10%. In one embodiment, the generated laser light
beam has a duty cycle of approximately 5% or less. The generated laser light
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beam may have a wavelength between 550nm and 1300nm. In one
embodiment, the generated laser light beam has a wavelength of approximately
810nm. The generated laser light beam may have an intensity of between 100-
590 watts per square centimeter at a treatment spot on the retina. The
generated laser light beam has a pulse length of less than 500 milliseconds.
[Para 22] The laser light beam may be manipulated into a geometric object
or pattern of simultaneously generated and spaced apart treatment laser light
spots with each spot having the intensity cited in paragraph 22. The
manipulated laser light beam may comprise the step of creating a
predetermined number of simultaneously generated laser light spots to
completely and confluently cover a desired treatment area. The geometric
object or pattern of laser light spots may cover substantially the entire
retina.
Alternatively, the geometric object or pattern of laser light spots may be
controllably moved to treat adjacent retinal tissue. The moving step may
include the step of incrementally moving the laser light beam geometric object
or pattern a sufficient distance from where the laser light beam geometric
object or pattern was previously applied to the retina to preclude thermal
tissue
damage.
[Para 23] The retina may be retreated periodically. The retreating of the
retina may be according to a set schedule. Additionally, or alternatively,
visual
and/or retinal function or condition of the patient is monitored to determine
when the retina of the patient is to be retreated.
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[Para 24] Other features and advantages of the present invention will
become
apparent from the following more detailed description, taken in conjunction
with the accompanying drawings, which illustrate, by way of example, the
principles of the invention.
Heading
BRIEF DESCRIPTION OF THE PREFERRED EMBODIMENTS
[Para 25] The accompanying drawings illustrate the invention. In such
drawings:
[Para 26] FIGURE 1 is a cross-sectional diagrammatic view of a human eye;
[Para 27] FIGURES 2A-2D are graphic representations of an effective surface
area of various modes of retinal laser treatment performed in accordance with
the prior art;
[Para 28] FIGURES 3A and 3B are graphic representations of effective
surface
areas of retinal laser treatment, in accordance with the present invention;
[Para 29] FIGURE 4 is a diagrammatic view illustrating a system used to
generate a laser light beam and treat an eye, in accordance with the present
invention;
[Para 30] FIGURE 5 is a diagrammatic view of optics used to generate a
laser
light geometric pattern, in accordance with the present invention;
[Para 31] FIGURE 6 is a diagrammatic view illustrating an alternate
embodiment of a system used to generate laser light beams for treating an eye,
in accordance with the present invention;
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[Para 32] FIGURE 7 is a diagrammatic view illustrating yet another
embodiment of a system used to generate laser light beams to treat an eye in
accordance with the present invention;
[Para 33] FIGURE 8 is a top plan view of an optical scanning mechanism,
used
in accordance with the present invention;
[Para 34] FIGURE 9 is a partially exploded view of the optical scanning
mechanism of FIG. 8, illustrating various component parts thereof; and
[Para 35] FIGURE 10 is a diagrammatic view illustrating the offsetting of a
geometric pattern of laser spots over multiple exposures so as to
substantially
cover an area of the eye being treated, in accordance with the present
invention.
Heading
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[Para 36] As shown in the accompanying drawings, for purposes of
illustration, the present invention is directed to a therapeutic process for
treating an eye to stop or delay the onset or symptoms of retinal diseases,
including chronic progressive retinal diseases, such as diabetic retinopathy
(DR)
and age-related macular degeneration (AMD).
[Para 37] As discussed above, it is conventional thinking that tissue
damage
and lesions must be created by retinal laser therapy in order to have a
therapeutic effect. However, the inventors have found that this simply not the
case and have shown that such thermal retinal damage is unnecessary and have
questioned whether it accounts for the benefits of the conventional laser
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treatments. The inventors have found that the therapeutic alterations in the
retinal pigment epithelium (RPE) cytokine production elicited by conventional
photocoagulation comes from cells at the margins of traditional laser burns,
effected but not killed by the laser exposure, referred to by the reference
number 26 in FIGS. 2A-2C.
[Para 38] The inventors have found that a laser light beam can be generated
that is therapeutic, yet sublethal to retinal tissue cells and thus creates
"true
subthreshold" photocoagulation in the retinal tissue which provides
preventative and protective treatment of the retinal tissue of the eye. The
inventors have discovered that generating a subthreshold, sublethal micropulse
laser light beam which has a wavelength greater than 532nm and a duty cycle
of less than 10% at a predetermined intensity or power and a predetermined
pulse length or exposure time creates desirable retinal photocoagulation,
shown by the reference number 28 in FIGS. 3A and 3B, without any visible burn
areas or tissue destruction. More particularly, a laser light beam having a
wavelength of between 550nm-1300nm, and in a particularly preferred
embodiment 810nm, having a duty cycle of approximately 5% or less and a
predetermined intensity or power (such as between 100-590 watts per square
centimeter for each treatment spot at the retina) and a predetermined pulse
length or exposure time (such as 500 milliseconds or less) creates a
sublethal,
"true subthreshold" retinal photocoagulation in which all areas of the retinal
pigment epithelium exposed to the laser irradiation are preserved and
available
to contribute therapeutically. In other words, the inventors have found that
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raising the retinal tissue at least up to a therapeutic level but below a
cellular or
tissue lethal level recreates the benefit of the halo effect (referred to by
the
reference number 26 in FIGS. 2A-2C) without destroying, burning or otherwise
damaging the retinal tissue. This is referred to herein as subthreshold diode
micropulse laser treatment (SDM).
[Para 39] FIGURE 3A represents a low-density treatment of the sublethal,
"true subthreshold" SDM or low-intensity laser, such as a micropulsed laser,
spots applied to retinal tissue 18 to create sublethal, subthreshold retinal
photostimulation, shown by the reference number 28, without any visible burn
areas. As SDM does not produce laser-induced retinal damage
(photocoagulation), and has no known adverse treatment effect, and has been
reported to be an effective treatment in a number of retinal disorders
(including
diabetic macular edema (DME) proliferative diabetic retinopathy (PDR), macular
edema due to branch retinal vein occlusion (BRVO), and central serous
chorioretinopathy (CSR) the present invention can be performed in a high-
density manner, as illustrated in FIG. 3B so as to essentially cover the
entire
treatment area, and even the entire retina, including the fovea. Traditional
and
conventional laser photocoagulation treatment is unable to treat the entire
retina, including the fovea, as the inherent burns and damage caused by the
treatment can impair the vision of the patient or even cause blindness.
[Para 40] By definition, SDM does not cause tissue damage and has no
known adverse treatment effect. SDM has been reported to be an effective
treatment in a number of retinal disorders, including DME, proliferative
diabetic
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retinopathy (PDR), macular edema due to branch retinal vein occlusion (BRVO),
and central serous chorioretinopathy (CSR). The safety of SDM is such that it
may be used transfoveally in eyes with 20/20 visual acuity to reduce the risk
of
visual loss due to early fovea-involving DME. It is believed that SDM works by
targeting, preserving, and normalizing - moving toward normal - function of
the RPE.
[Para 41] Another mechanism through which SDM might work is the
generation of heat shock proteins (HSPs). Despite a near infinite variety of
possible cellular abnormalities, cells of all types share a common and highly
conserved mechanism of repair: heat shock proteins (HSPs). HSPs are elicited
almost immediately, in seconds to minutes, by almost any type of cell stress
or
injury. In the absence of lethal cell injury, HSPs are extremely effective at
repairing and returning the viable cell toward a more normal functional state.
Although HSPs are transient, generally peaking in hours and persisting for a
few
days, their effects may be long lasting. HSPs reduce inflammation, a common
factor in many retinal disorders, including diabetic retinopathy (DR) and AMD.
[Para 42] Laser treatment induces HSP production and, in the case of
retinal
treatment, alters retinal cytokine expression. The more sudden and severe the
non-lethal cellular stress (such as laser irradiation), the more rapid and
robust
HSP production. Thus, a burst of repetitive low temperature thermal spikes at
a
very steep rate of change (¨ 20 C elevation with each 100ps micropulse, or
20,000 C/sec) produced by each SDM exposure is especially effective in
stimulating production of HSPs, particularly compared to non-lethal exposure
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to subthreshold treatment with continuous wave lasers, which can duplicate
only the low average tissue temperature rise.
[Para 43] Laser wavelengths below 550nm produce increasingly cytotoxic
photochemical effects. At 810nm, SDM produces photothermal, rather than
photochemical, cellular stress. Thus, SDM is able to affect the tissue,
including
RPE, without damaging it. Consistent with HSP activation, SDM produces prompt
clinical effects, such as rapid and significant improvement in retinal
electrophysiology, visual acuity, contrast visual acuity and improved macular
sensitivity measured by microperimetry, as well as long-term effects, such as
reduction of DME and involution of retinal neovascularization.
[Para 44] In the retina, the clinical benefits of SDM are thus produced by
sub-morbid photothermal RPE HSP activation. In dysfunctional RPE cells, HSP
stimulation by SDM results in normalized cytokine expression, and
consequently improved retinal structure and function. The therapeutic effects
of this "low-intensity" laser/tissue interaction are then amplified by "high-
density" laser application, recruiting all the dysfunctional RPE in the
targeted
area, thereby maximizing the treatment effect. These principles define the
treatment strategy of SDM described herein. The ability of SDM to produce
therapeutic effects similar to both drugs and photocoagulation indicates that
laser-induced retinal damage (for effects other than cautery) is unnecessary
and non-therapeutic; and, in fact, detrimental because of the loss of retinal
function and incitement of inflammation.
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[Para 45] Because normally functioning cells are not in need of repair, HSP
stimulation in normal cells would tend to have no notable clinical effect. The
"patho-selectivity" of near infrared laser effects, such as SDM, affecting
sick
cells but not affecting normal ones, on various cell types is consistent with
clinical observations of SDM. This facility is key to the suitability of SDM
for
early and preventative treatment of eyes with chronic progressive disease and
eyes with minimal retinal abnormality and minimal dysfunction. Finally, SDM
has been reported to have a clinically broad therapeutic range, unique among
retinal laser modalities, consistent with American National Standards
Institute
"Maximum Permissible Exposure" predictions. While SDM may cause direct
photothermal effects such as entropic protein unfolding and disaggregation,
SDM appears optimized for clinically safe and effective stimulation of HSP-
mediated retinal repair.
[Para 46] As noted above, while SDM stimulation of RPE HSPs is non-specific
with regard to the disease process, the result of HSP mediated repair is by
its
nature specific to the state of the dysfunction. HSPs tend to fix what is
wrong,
whatever that might be. Thus, the observed effectiveness of SDM in retinal
conditions as widely disparate as BRVO, DME, PDR, CSR, and drug-tolerant
NAMD. Conceptually, this facility can be considered a sort of "Reset to
Default"
mode of SDM action. For the wide range of retinal disorders in which RPE
function is critical, SDM normalizes RPE function by triggering a "reset" (to
the
"factory default settings") via HSP-mediated cellular repair. Certainly, SDM
has
limitations. For instance, clinical experience with this theory suggests that
SDM
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is less effective once RPE mediated disease-related anatomic derangement,
such as in chronic cystoid macular edema, retinal atrophy and scarring, or the
pathologic environment, is so severe and/or degenerative that the retina can
no
longer respond to RPE autoregulatory influences. That absence of sufficient
viable target RPE due to severe pigmentary atrophy may preclude a treatment
response.
[Para 47] The inventors have found that SDM treatment of patients suffering
from age-related macular degeneration (AMD) can slow the progress or even
stop the progression of AMD. Most of the patients have seen significant
improvement in dynamic functional logMAR visual acuity and contrast visual
acuity after the SDM treatment, with some experiencing better vision. It is
believed that SDM works by targeting, preserving, and "normalizing" (moving
toward normal) function of the retinal pigment epithelium (RPE).
[Para 48] SDM has also been shown to stop or reverse the manifestations of
the diabetic retinopathy disease state without treatment-associated damage or
adverse effects, despite the persistence of systemic diabetes mellitus. On
this
basis it is hypothesized that SDM might work by inducing a return to more
normal cell function and cytokine expression in diabetes-affected RPE cells,
analogous to hitting the "reset" button of an electronic device to restore the
factory default settings.
[Para 49] Based on the above information and studies, SDM treatment may
directly affect cytokine expression and heat shock protein (HSP) activation in
the targeted tissue, particularly the retinal pigment epithelium (RPE) layer.
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Panretinal and panmacular SDM has been noted by the inventors to reduce the
rate of progression of many retinal diseases, including severe non-
proliferative
and proliferative diabetic retinopathy, AMD, DME, etc. The known therapeutic
treatment benefits of individuals having these retinal diseases, coupled with
the
absence of known SDM adverse treatment effects, allows for consideration of
early and preventative treatment, liberal application and retreatment as
necessary. The reset theory also suggests that SDM may have application to
many different types of RPE-mediated retinal disorders. In fact, the inventor
has
recently shown that panmacular SDM can significantly improve retinal function
and health, retinal sensitivity, and dynamic logMAR visual acuity and contrast
visual acuity in dry age-related macular degeneration, retinitis pigmentosa,
cone-rod retinal degenerations, and Stargardt's disease where no other
treatment has previously been found to do so.
[Para 50] Currently, retinal imaging and visual acuity testing guide
management of chronic, progressive retinal diseases. As tissue and/or organ
structural damage and vision loss are late disease manifestations, treatment
instituted at this point must be intensive, often prolonged and expensive, and
frequently fails to improve visual acuity and rarely restores normal vision.
As
SDM has been shown to be an effective treatment for a number of retinal
disorders without adverse treatment effects, and by virtue of its safety and
effectiveness, SDM can also be used to treat an eye to stop or delay the onset
or
symptoms of retinal diseases prophylactically or as a preventative treatment
for
such retinal diseases. Any treatment that improves retinal function, and thus
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health, should also reduce disease severity, progression, untoward events and
visual loss. By beginning treatment early, prior to pathologic structural
change,
and maintaining the treatment benefit by regular functionally-guided re-
treatment, structural degeneration and visual loss might thus be delayed if
not
prevented. Even modest early reductions in the rate of disease progression
may lead to significant long-term reductions and complications in visual loss.
By mitigating the consequences of the primary defect, the course of disease
may be muted, progression slowed, and complications and visual loss reduced.
[Para 51] In accordance with the present invention, it is determined that a
patient, and more particularly an eye of the patient, has a risk for a retinal
disease. This may be before retinal imaging abnormalities are detectable. Such
a determination may be accomplished by ascertaining if the patient is at risk
for
a chronic progressive retinopathy, including diabetes, a risk for age-related
macular degeneration or retinitis pigmentosa. Alternatively, or additionally,
results of a retinal examination or retinal test of the patient may be
abnormal.
A specific test, such as a retinal physiology test or a genetic test, may be
conducted to establish that the patient has a risk for a retinal disease.
[Para 52] An SDM laser light beam, that is sublethal and creates true
subthreshold photocoagulation and retinal tissue, is generated and at least a
portion of the retinal tissue is exposed to the generated laser light beam
without damaging the exposed retinal or foveal tissue, so as to provide
preventative and protective treatment of the retinal tissue of the eye. The
treated retina may comprise the fovea, foveola, retinal pigment epithelium,
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choroid, choroidal neovascular membrane, subretinal fluid, macula, macular
edema, parafovea, and/or perifovea. The laser light beam may be exposed to
only a portion of the retina, or substantially the entire retina and fovea.
[Para 53] While most SDM effects appear to be long-lasting, if not
permanent, clinical observations suggest that SDM can appear to wear off on
occasion. Accordingly, the retina is periodically retreated. This may be done
according to a set schedule or when it is determined that the retina of the
patient is to be retreated, such as by periodically monitoring visual and/or
retinal function or condition of the patient.
[Para 54] With reference now to FIG. 4, a schematic diagram is shown of a
system for realizing the process of the present invention. The system,
generally referred to by the reference number 30, includes a laser console 32,
such as for example the 810nm near infrared micropulsed diode laser in the
preferred embodiment. The laser generates a laser light beam which is passed
through optics, such as an optical lens or mask, or a plurality of optical
lenses
and/or masks 34 as needed. The laser projector optics 34 pass the shaped
light beam to a coaxial wide-field non-contact digital optical viewing
system/camera 36 for projecting the laser beam light onto the eye 38 of the
patient. It will be understood that the box labeled 36 can represent both the
laser beam projector as well as a viewing system/camera, which might in
reality
comprise two different components in use. The viewing system/camera 36
provides feedback to a display monitor 40, which may also include the
necessary computerized hardware, data input and controls, etc. for
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manipulating the laser 32, the optics 34, and/or the projection/viewing
components 36.
[Para 55] With reference now to FIG. 5, in one embodiment, the laser light
beam 42 is passed through a collimator lens 44 and then through a mask 46.
In a particularly preferred embodiment, the mask 46 comprises a diffraction
grating. The mask/diffraction grating 46 produces a geometric object, or more
typically a geometric pattern of simultaneously produced multiple laser spots
or
other geometric objects. This is represented by the multiple laser light beams
labeled with reference number 48. Alternatively, the multiple laser spots may
be generated by a plurality of fiber optic wires. Either method of generating
laser spots allows for the creation of a very large number of laser spots
simultaneously over a very wide treatment field, such as consisting of the
entire
retina. In fact, a very high number of laser spots, perhaps numbering in the
hundreds even thousands or more could cover the entire ocular fundus and
entire retina, including the macula and fovea, retinal blood vessels and optic
nerve. The intent of the process in the present invention is to better ensure
complete and total coverage and treatment, sparing none of the retina by the
laser so as to improve vision.
[Para 56] Using optical features with a feature size on par with the
wavelength of the laser employed, for example using a diffraction grating, it
is
possible to take advantage of quantum mechanical effects which permits
simultaneous application of a very large number of laser spots for a very
large
target area. The individual spots produced by such diffraction gratings are
all
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of a similar optical geometry to the input beam, with minimal power variation
for each spot. The result is a plurality of laser spots with adequate
irradiance to
produce harmless yet effective treatment application, simultaneously over a
large target area. The present invention also contemplates the use of other
geometric objects and patterns generated by other diffractive optical
elements.
[Para 57] The laser light passing through the mask 46 diffracts, producing
a
periodic pattern a distance away from the mask 46, shown by the laser beams
labeled 48 in FIG. 5. The single laser beam 42 has thus been formed into
hundreds or even thousands of individual laser beams 48 so as to create the
desired pattern of spots or other geometric objects. These laser beams 48 may
be passed through additional lenses, collimators, etc. 50 and 52 in order to
convey the laser beams and form the desired pattern on the patient's retina.
Such additional lenses, collimators, etc. 50 and 52 can further transform and
redirect the laser beams 48 as needed.
[Para 58] Arbitrary patterns can be constructed by controlling the shape,
spacing and pattern of the optical mask 46. The pattern and exposure spots
can be created and modified arbitrarily as desired according to application
requirements by experts in the field of optical engineering. Photolithographic
techniques, especially those developed in the field of semiconductor
manufacturing, can be used to create the simultaneous geometric pattern of
spots or other objects.
[Para 59] FIG. 6 illustrates diagrammatically a system which couples
multiple
light sources into the pattern-generating optical subassembly described above.
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Specifically, this system 30' is similar to the system 30 described in FIG. 4
above. The primary differences between the alternate system 30' and the
earlier described system 30 is the inclusion of a plurality of laser consoles
32,
the outputs of which are each fed into a fiber coupler 54. The fiber coupler
produces a single output that is passed into the laser projector optics 34 as
described in the earlier system. The coupling of the plurality of laser
consoles
32 into a single optical fiber is achieved with a fiber coupler 54 as is known
in
the art. Other known mechanisms for combining multiple light sources are
available and may be used to replace the fiber coupler described herein.
[Para 60] In this system 30' the multiple light sources 32 follow a similar
path as described in the earlier system 30, i.e., collimated, diffracted,
recollimated, and directed into the retina with a steering mechanism. In this
alternate system 30' the diffractive element must function differently than
described earlier depending upon the wavelength of light passing through,
which results in a slightly varying pattern. The variation is linear with the
wavelength of the light source being diffracted. In general, the difference in
the
diffraction angles is small enough that the different, overlapping patterns
may
be directed along the same optical path through the steering mechanism 36 to
the retina 38 for treatment. The slight difference in the diffraction angles
will
affect how the steering pattern achieves coverage of the retina.
[Para 61] Since the resulting pattern will vary slightly for each
wavelength, a
sequential offsetting to achieve complete coverage will be different for each
wavelength. This sequential offsetting can be accomplished in two modes. In
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the first mode, all wavelengths of light are applied simultaneously without
identical coverage. An offsetting steering pattern to achieve complete
coverage
for one of the multiple wavelengths is used. Thus, while the light of the
selected wavelength achieves complete coverage of the retina, the application
of the other wavelengths achieves either incomplete or overlapping coverage of
the retina. The second mode sequentially applies each light source of a
varying
wavelength with the proper steering pattern to achieve complete coverage of
the retina for that particular wavelength. This mode excludes the possibility
of
simultaneous treatment using multiple wavelengths, but allows the optical
method to achieve identical coverage for each wavelength. This avoids either
incomplete or overlapping coverage for any of the optical wavelengths.
[Para 62] These modes may also be mixed and matched. For example, two
wavelengths may be applied simultaneously with one wavelength achieving
complete coverage and the other achieving incomplete or overlapping coverage,
followed by a third wavelength applied sequentially and achieving complete
coverage.
[Para 63] FIG. 7 illustrates diagrammatically yet another alternate
embodiment of the inventive system 30". This system 30" is configured
generally the same as the system 30 depicted in FIG. 4. The main difference
resides in the inclusion of multiple pattern-generating subassembly channels
tuned to a specific wavelength of the light source. Multiple laser consoles 32
are arranged in parallel with each one leading directly into its own laser
projector optics 34. The laser projector optics of each channel 58a, 58b, 58c
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comprise a collimator 44, mask or diffraction grating 48 and recollimators 50,
52 as described in connection with FIG. 5 above - the entire set of optics
tuned
for the specific wavelength generated by the corresponding laser console 32.
The output from each set of optics 34 is then directed to a beam splitter 56
for
combination with the other wavelengths. It is known by those skilled in the
art
that a beam splitter used in reverse can be used to combine multiple beams of
light into a single output.
[Para 64] The combined channel output from the final beam splitter 56c is
then directed through the camera 36 which applies a steering mechanism to
allow for complete coverage of the retina 38.
[Para 65] In this system 30" the optical elements for each channel are
tuned
to produce the exact specified pattern for that channel's wavelength.
Consequently, when all channels are combined and properly aligned a single
steering pattern may be used to achieve complete coverage of the retina for
all
wavelengths.
[Para 66] The system 30" may use as many channels 58a, 58b, 58c, etc. and
beam splitters 56a, 56b, 56c, etc. as there are wavelengths of light being
used
in the treatment.
[Para 67] Implementation of the system 30" may take advantage of different
symmetries to reduce the number of alignment constraints. For example, the
proposed grid patterns are periodic in two dimensions and steered in two
dimensions to achieve complete coverage. As a result, if the patterns for each
channel are identical as specified, the actual pattern of each channel would
not
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need to be aligned for the same steering pattern to achieve complete coverage
for all wavelengths. Each channel would only need to be aligned optically to
achieve an efficient combination.
[Para 68] In system 30", each channel begins with a light source 32, which
could be from an optical fiber as in other embodiments of the pattern-
generating subassembly. This light source 32 is directed to the optical
assembly 34 for collimation, diffraction, recollimation and directed into the
beam splitter which combines the channel with the main output.
[Para 69] Typically, the system of the present invention incorporates a
guidance system to ensure complete and total retinal treatment with retinal
photostimulation. As the treatment method of the present invention is
harmless, the entire retina, including the fovea and even optical nerve, can
be
treated. Moreover, protection against accidental visual loss by accidental
patient movement is not a concern. Instead, patient movement would mainly
affect the guidance in tracking of the application of the laser light to
ensure
adequate coverage. Fixation/tracking/registration systems consisting of a
fixation target, tracking mechanism, and linked to system operation are
common in many ophthalmic diagnostic systems and can be incorporated into
the present invention.
[Para 70] With reference now to FIGS. 8 and 9, in a particularly preferred
embodiment, the geometric pattern of simultaneous laser spots is sequentially
offset so as to achieve confluent and complete treatment of the retinal
surface.
Although a segment of the retina can be treated in accordance with the present
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invention, more ideally the entire retina will be treated with one treatment.
This
is done in a time-saving manner by placing hundreds to thousands of spots
over the entire ocular fundus at once. This pattern of simultaneous spots is
scanned, shifted, or redirected as an entire array sequentially, so as to
cover the
entire retina.
[Para 71] This can be done in a controlled manner using an optical scanning
mechanism 60. FIGS. 8 and 9 illustrate an optical scanning mechanism 60 in
the form of a MEMS mirror, having a base 62 with electronically actuated
controllers 64 and 66 which serve to tilt and pan the mirror 68 as electricity
is
applied and removed thereto. Applying electricity to the controller 64 and 66
causes the mirror 68 to move, and thus the simultaneous pattern of laser spots
or other geometric objects reflected thereon to move accordingly on the retina
of the patient. This can be done, for example, in an automated fashion using
electronic software program to adjust the optical scanning mechanism 60 until
complete coverage of the retina, or at least the portion of the retina desired
to
be treated, is exposed to the phototherapy. The optical scanning mechanism
may also be a small beam diameter scanning galvo mirror system, or similar
system, such as that distributed by Thorlabs. Such a system is capable of
scanning the lasers in the desired offsetting pattern.
[Para 72] With reference now to FIG. 10, a diagrammatic representation of
the process of sequentially offsetting laser spots is shown. A geometric
pattern
of laser spots is shown in an initial exposure 1, the geometric pattern is
offset
and the retina is exposed again in exposure 2, wherein the current exposure is
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shown by the circles and the prior exposure(s) shown and represented by the
solid dots. The spacing of the laser spots prevents overheating and damage to
the tissue. This is repeated over multiple exposures until the entire
treatment
area, or even the entire retina, has been exposed to the SDM laser treatment.
In this manner a low-density treatment, as illustrated in FIG. 3A, can become
a
high-density treatment, as illustrated in FIG. 3B. Of course, however, the
optics
and number of laser spots generated and the distance between laser spots
could be such that an entire treatment area, or even the entire retina, could
be
exposed simultaneously with only a single exposure.
[Para 73] The invention described herein is generally safe for panretinal
and/or trans-foveal treatment. However, it is possible that a user, i.e.,
surgeon, preparing to limit treatment to a particular area of the retina where
disease markers are located or to prevent treatment in a particular area with
darker pigmentation, such as from scar tissue.
[Para 74] The American Standards Institute (ANSI) has developed standards
for safe workplace laser exposure based on the combination of theoretical and
empirical data. The "maximum permissible exposure" (MPE) is the safety level,
set at approximately 1/10th of the laser exposure level expected to produce
biological effects. At a laser exposure level of 1 times MPE, absolute safety
would be expected and retinal exposure to laser radiation at this level would
be
expected to have no biologic affect. Based on ANSI data, a 50% of some risk of
suffering a barely visible (threshold) burn is generally encountered at 10
times
MPE for conventional continuous wave laser exposure. For a low-duty cycle
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micropulsed laser exposure of the same power, the risk of threshold burn is
approximately 100 times MPE. Thus, the therapeutic range - the interval of
doing nothing at all and the 50% of some likelihood of producing a threshold
burn - for low-duty cycle micropulsed laser irradiation is 10 times wider than
for continuous wave laser irradiation with the same energy. It has been
determined that safe and effective sublethal, true subthreshold
photocoagulation using a micropulsed diode laser is between 18 times and 55
times MPE, with a preferred laser exposure, for example, to retinal tissue at
47
times MPE for a near-infrared 810nm diode laser. At this level, it has been
observed that there is therapeutic effectiveness with no discernible retinal
damage whatsoever.
[Para 75] It has been found that the intensity or power of a laser between
100 watts to 590 watts, and preferably 350 watts, per square centimeter at a
retinal treatment spot is effective yet safe. A particularly preferred
intensity or
power of the laser light is approximately one watt per laser spot for an 810nm
micropulsed diode laser.
[Para 76] Power limitations in current micropulsed diode lasers require
fairly
long exposure duration. The longer the exposure, the more important the
center-spot heat dissipating ability toward the unexposed tissue at the
margins
of the laser spot and toward the underlying choriocapillaris as in the retina.
Thus, the micropulsed laser light beam of an 810nm diode laser should have an
exposure envelope duration of 500 milliseconds or less, and preferably
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approximately 300 milliseconds. Of course, if micropulsed diode lasers
become more powerful, the exposure duration should be lessened accordingly.
[Para 77] Another parameter of the present invention is the duty cycle (the
frequency of the train of micropulses, or the length of the thermal relaxation
time in between consecutive pulses). It has been found that the use of a 10%
duty cycle or higher adjusted to deliver micropulsed laser at similar
irradiance
at similar MPE levels significantly increase the risk of lethal cell injury,
particularly in darker fundi. However, duty cycles less than 10%, and
preferably
approximately 5% duty cycle (or less, such as 2.5%) demonstrate adequate
thermal rise and treatment at the level of the MPE cell to stimulate a
biologic
response, but remain below the level expected to produce lethal cell injury,
even in darkly pigmented fundi. If the duty cycle is less than 5%, the
exposure
envelope duration in some instances can exceed 500 milliseconds.
[Para 78] In a particularly preferred embodiment, small laser spots are
used.
This is due to the fact that larger spots can contribute to uneven heat
distribution and insufficient heat dissipation within the large laser spot,
potentially causing tissue damage or even tissue destruction towards the
center
of the larger laser spot. In this usage, "small" would generally apply to
spots
less than 1mm in diameter. However, the smaller the spot, the more ideal the
heat dissipation and uniform energy application becomes. Thus, at the power
intensity and exposure duration described above, small spots, such as along
the size of the wavelength of the laser, or small geometric lines or other
objects
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are preferred so as to maximize even heat distribution and heat dissipation to
avoid tissue damage.
[Para 79] Thus, the following key parameters have been found in order to
create harmless, "true" subthreshold photocoagulation in accordance with the
present invention: a) a low (preferably 5% or less) duty cycle; b) a small
spot
size to minimize heat accumulation and assure uniform heat distribution within
a given laser spot so as to maximize heat dissipation; c) sufficient power to
produce laser exposures of between 18 times - 55 times MPE producing a
tissue temperature rise of no more than 7 C - 14 C; and irradiance of
between
100-590W/cm2.
[Para 80] Using the foregoing parameters, a harmless, "true" subthreshold
photocoagulation phototherapy treatment can be attained which has been
found to produce the benefits of conventional photocoagulation phototherapy,
but avoids the drawbacks and complications of conventional phototherapy. In
fact, sublethal, "true" subthreshold photocoagulation phototherapy in
accordance with the present invention enables the physician to apply a "low-
intensity/high-density" phototherapy treatment, for example as illustrated in
FIG. 38 for treatment of the entire retina, including sensitive areas such as
the
macula and even the fovea without creating visual loss or other damage. As
indicated above, using conventional phototherapies was impossible on the
entire retina, particularly the fovea, as it would create vision loss due to
the
tissue damage in sensitive areas at the retina.
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[Para 81] An analysis of the effectiveness and safety of the discussed SDM
treatment has been performed with approximations to the exact equations for
the laser absorption, heat diffusion, and Arrhenius reaction rates describing
the
process. Comparisons have also been made with the same approximate
equations for alternate approaches (CW and Pascal and nano-second CW laser
exposures). The following indicates that for typical operating parameters, SDM
is both safe and effective, whereas the alternate techniques can be either
ineffective or not safe.
[Para 82] Results for Arrhenius integrals from approximate equations:
Table 1. Four typical laser treatments:
Laser parameters Retinal spot Laser
power Exposure Duty Cycle
type diameter (pm) (mW) time (ms) (repeat rate)
Canonical SDM 131 950 300 5%
(500 Hz)
CW power equiv 131 47.5 300 100%
to SDM
CW temps equiv 131 37 300 100%
to SDM
CSMO Pascal 200 21.26 15 100%
[Para 83] In the first four cases, the laser wavelength is 810nm, while in
the
Pascal case, the wavelength is 532 nm. The absorption coefficient for 532 nm
is approximately 4 times that for 810 nm.
[Para 84] The Arrhenius integral results for damage and HSP production for
these four treatments are summarized in Table 2.
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[Para 85] Table 2. Arrhenius integral results for the treatments of Table 1
(using our approximate equations). dTp is the temperature rise of the first
pulse (and only pulse, for the 3 CW parameters). dToo' is the baseline
temperature rise of the pulse train for SDM. n(dmg) is the arrhenius integral
for damage using the Arrhenius rate parameters from the MPE data for
minimum retinal radius. n(HSP) is the Arrhenius integral for HSP stimulation.
For the 810nm cases, an experimentally-based optical transmission efficiency
of 80% has been assumed in calculating the temperature rises.
Laser parameters type dTp dToo' Q(dmg) Q(HSP)
Canonical SDM 8.78K 7.30K 0.024 2.01
CW power equiv to SDM 34.12K 22.1 346
CW temps equiv to SDM 7.37K 0.017 1.62
CSMO Pascal 7.13K 0.0012 0.14
Damage occurs when n(dmg) > 1, and HSP production occurs when n(HSP) >1.
Accordingly, the desired treatment result is for n(dmg) < 1 and n(HSP) >1.
[Para 86] As Table 2 shows, only the canonical SDM treatment and the CW
temperature equivalent to SDM accomplishes this.
[Para 87] Following such treatment with a high-density/low-intensity
subthreshold diode micropulse laser there may be treatment verification and
monitoring. Responses to the treatment described herein may be detectable by
retinal function testing pre-therapeutically. Such tests may include pattern
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electroretinography (PERG), microperimetry, and threshold micro-visual acuity
testing, which are all existing technologies. Such post-treatment, pre-
therapeutic retinal function testing allows for conformation of treatment
administration and effect. It also allows one to prospectively follow patients
to
determine the need for retreatment, indicated by worsening results of retinal
function testing. By combining retinal function testing with true-subthreshold
treatment allows for a treatment modality able to demonstrate a desired
immediate treatment effect absent detectable retinal damage. The retinal
function testing also allows for the prevention of disease progression by
detecting early on a need for re-treatment prophylactically.
[Para 88] Current retinal treatment measures are anatomic, meaning that
they are "late"-term indicators - abnormal only in advanced and end-stage
diseases. Using retinal function indicators that may improve in apparently
normal eyes prior to the development of anatomic changes can help document
treatment benefits in the absence of anatomic derangement. The retinal
function testing can be used to signal the need for re-treatment prior to the
development of anatomic disease. The ability to prevent clinical/anatomic
disease, vision loss, and the need for more intensive and expensive treatments
can be rationally minimized.
[Para 89] The process and methodology of the present invention has been
the subject of an initial experimental trial study. The invention was offered
as a
prophylaxis/retinal protection for high-risk AMD and inherited degenerations
(IRD). Testing was performed within one week prior to SDM treatment and
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within one month after treatment. The results of retinal and visual function
testing in a group of those patients evaluated before and after SDM
prophylaxis
by pattern electroretinography (PERG), automated microperimetry (AMP) and
central vision analyzer (CVA) testing.
[Para 90] PERG was performed using standard protocols of a commercially
available system (Diopsyse Nova-ERG, Diopsys Corp., Pine Brook, New Jersey)
according to International Society for Clinical Electrophysiology of Vision
standards. Both eyes were tested simultaneously and recorded individually,
undilated, and refracted for a 60 cm testing distance. For all visual stimuli,
a
luminance pattern occupying a 25 visual field is presented with a luminance
reversal rate of 15 Hz.
[Para 91] For IRD, a PERG "Concentric Ring" (CR) visual stimulus optimized
for analyzing peripheral retinal sensitivity was employed, presenting with a
circle of one luminance and an outer ring with the contrasting luminance. The
concentric ring stimulus used two sub-classes of stimuli with an inner circle
occupying a visual field of 16 and 24 , respectively. The concentric ring
stimuli
used a mean luminance of 117.6 cd/m2 with a contrast of 100%.
[Para 92] For AMD, in addition to the CR scans, Contrast Sensitivity (CS)
stimuli were employed, presenting a grid of 64 x 64 cells, alternating
luminance
levels, recording a high contrast (HC) test with a mean luminance of 112 cd/m2
and a contrast of 85%, and a low contrast (LC) test with a mean luminance of
106.4 cd/m2 and a contrast of 75%.
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[Para 93] Patient and equipment preparation were carried out according to
DiopsysTM guidelines. Signal acquisition and analysis followed a standard
glaucoma screening protocol. Test indices available for analysis included
"Magnitude D", "Magnitude (pV)", and the "MagD(pV)/Mag(pV)" ratio.
"Magnitude D" [MagD(pV)] is the frequency response of the time-domain
averaged signal in microvolts (pV). Macular and/or ganglion cell dysfunction
cause signal latencies resulting in magnitude and phase variability that
reduce
MagD by phase cancelation. Magnitude (pV) [Mag(pV)] measures the frequency
response of the total signal in microvolts (pV). Mag (pV) reflects the signal
strength and electrode impedance of the individual test sessions, as well as a
gross measure of ganglion function. The MagD(pV)/Mag(pV) ratio thus provides
a measure of patient response normalized to that particular test's electrical
quality. The closer MagD(pV)/Mag(pV) to unity, the more normal macular
function.
[Para 94] AMP (MAIA, Centervue Inc, Fremont, CA) testing was performed
without dilation or anesthesia, according to manufacturer recommendations.
Data recorded included percent-reduced thresholds, average threshold, and
percent primary and secondary fixation localization.
[Para 95] CVA (Visoptics, Mechanicsberg, PA) is an FDA approved measure of
visual acuity. A thresholding algorithm is used to dynamically determine
logMAR central visual acuity for 6 different levels of contrast, ranging from
99%
to 35%, using an interactive computer interface.
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[Para 96] Following informed consent and pupillary dilation, topical
proparacaine was applied to the cornea. A Mainster macular contact lens
(Ocular Instruments, Mentor, Ohio, magnification factor 1.05x) was placed on
the cornea with the aid of viscoelastic. Under minimum slit-lamp illumination,
the entire posterior retina circumscribed by the major vascular arcades was
"painted" with] 800-3000 confluent spot applications of SDM ("panmacular"
treatment). The laser parameters used were 810nm wavelength, 200um aerial
spot size, 5% duty cycle; and 1.6 watt power and 0.075 second duration
(Oculight SLx, Iris Medical / Index Corp, Mountain View, California).
[Para 97] All data was anonym ized prior to statistical analysis. AM
analyses
were performed using linear mixed models predicting the measure, with an
indicator for time as a covariate, adjusting for left or right eye, and
including a
random patient intercept to correct for possible inter-eye correlation.
Finally,
univariate linear mixed models, predicting the difference (post- minus pre-
treatment) with pre-treatment value as covariate were performed. The
coefficients and p-values from six such models were compared.
[Para 98] In the following, "macular function" and "retinal function" refer
to
the physiology and electrophysiology of the retina. In contrast, "visual
function"
is used to refer to measurements such as visual acuity, visual fields, and
contrast sensitivity,
[Para 99] 220 eyes of 166 patients undergoing panmacular SDM prophylaxis for
high-risk AMD and IRD were identified. These included 210 eyes of 158
patients treated for AMD; and 10 eyes of 8 patients treated for IRD. Of these,
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167 consecutive eyes of 108 patients with AMD, and 10 consecutive eyes of 8
patients with IRD were evaluated before and after SDM by PERG and thus
eligible for study. IRD diagnoses included rod-cone degeneration (4 eyes),
cone-rod degeneration (3 eyes), and Stargardt's disease (3 eyes). Visual
function testing was performed in 113 consecutive AMD eyes concurrently with
PERG; including AMP in 40 consecutive eyes, and CVA testing in the subsequent
73 consecutive eyes.
[Para 100] Overall, 149/168 eyes were improved by PERG after SDM. Snellen
visual acuities, ranging from 20/20 to CF preoperatively, were unchanged.
Patients with geographic atrophy frequently reported prompt subjective
lightening or disappearance of their prior central scotoma. There were no
adverse treatment effects.
[Para 101] 139/158 eyes with high-risk dry AMD were improved by PERG
following SDM. Post SDM CS HC MagD(uV)/Mag(uV) ratios were not significantly
improved (P=0.09). However, CS LC MagD(uV)/Mag(uV) ratios (P=0.0001) and
CS LC MagD(uV) amplitudes (P=0.02) were significantly improved.
[Para 102] Table 3. Comparison of various measured values (Post- minus Pre-
Treatment), PERG Contrast Sensitivity Test eyes, for high-risk age-related
macular degeneration in response to panmacular SDM laser retinal protective
therapy.
iiii.iyarfabjemoiniginimminigiummeNoiairtiZpyiniminiMedlaniMninigivolajuemum
M(d)/M(uv) Ratio, High 0.05 (0.19) 0.04 (-0.07, 0.09
Contrast 0.17)
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M(d) Measure, High Contrast 0.05 (0.32) 0.05 (-0.17, 0.37
0.26)
NiM(d) MOasuremLOWCWitrastimmiNO&(0KZ5)0W7g(gMOMOgi
021)
M(uv) Measure, High -0.04 (0.34) -0.04 (-0.23, 0.42
Contrast 0.14)
M(uu).Measiiire.Lovweci.intras0.i.A1K(Ik33)*()AP(okt9CL&Ng
[Para 103] Table 3 shows the comparisons of interest for the PERG Contrast
Sensitivity Test dataset. Each row shows the difference (post- minus pre-
treatment) in M(d)/M(uv) ratio, M(d) measure, or M(uv) measure, at the two
contrast options. In order to test whether the mean difference is different
from
zero, linear mixed models predicting the measure, using an indicator for time
as a covariate, also adjusting for left or right eye, and including a random
patient intercept, were performed. The p-values are those associated with the
time (pre- versus post-) regression coefficient. A significant p-value
indicates
that the mean difference is significantly different from zero. The table shows
that M(d)/M(uv) ratio, low contrast, as well as M(d) measure, low contrast,
are
significantly higher post-treatment compared to pre-treatment (positive values
indicate higher post-treatment values, negative values indicate higher pre-
treatment values). This method accounts for inter-eye correlation.
[Para 104] Table 4. Comparison of various measured values (Post- minus Pre-
Treatment), Concentric Ring Scan eyes with high-risk age-related macular
degeneration treated with panmacular SDM laser retinal protective therapy.
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M(d)/M(uv) Ratio, 24 Degree 0.02 (0.21) 0.01 (-0.09, 0.44
0.12)
giM(d)1M(tiv)RatioptDegreak(M22):MCfiTi(At10 007
M(d) Measure, 24 Degree 0.04 (0.38) 0.02 (-0.20, 0.52
0.23)
M(uv) Measure, 24 Degree 0.01 (0.36) 0.00 (-0.18, 0.86
0.20)
FM(uv)*10astoreViifiint.greemum*MOCCM36.0Mlit4lh.ZtonurOtim
[Para 105] Table 4 shows the comparisons of interest for the PERG Concentric
Ring Test dataset. Each row shows the difference (first post-treatment minus
pre-treatment) in M(d)/M(uv) ratio, M(d) measure, or M(uv) measure, at the 24
and 16 degrees. In order to test whether the mean difference is different from
zero, linear mixed models predicting the measure were performed, using an
indicator for time as a covariate, also adjusting for left or right eye, and
including a random patient intercept. The p-values are those associated with
the time (pre- versus post-) regression coefficient. A significant p-value
indicates that the mean difference is significantly different from zero. The
table
shows that all comparisons are not statistically significant. This method
accounts for inter-eye correlation.
[Para 106] 10/10 eyes with 1RD improved by PERG following SDM. CR 16
testing was not improved (P=0.19), but CR 24 (MagD(uV)/Mag(uV) ratios
(P=0.002) and MagD(uV) amplitudes (P=0.006) were both improved.
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[Para 107] Table 5. Comparison of various measured values (Post- minus Pre-
Treatment) eyes with heritable retinal disorders treated by panmacular SDM
retinal protection.
...............................................................................
...............................................................................
...............................................................................
............................................
...............................................................................
...............................................................................
...............................................................................
............................................
Variable Mean Median (IQR) p- Mean Median (IQR) p-
Mean Median (IQR)
(SD) value a (SD) value a (SD)
va
...............................................................................
...............................................................................
...............................................................................
............................................
M(uv) Ratio, 16 0.07 0.06 (-0.01, 0.08 0.08 0.07
(0.00, 0.19 0.06 0.06 (-0.01, 0.2
(0.18) 0.16) (0.22) 0.33) (0.09) 0.14)
N.;.iii.14I111$11116iiiii1111111111116.1116111111111111111111111111110111651511
111111111111151=111111115111i11111111111111111111111111.11111111111111111111111
1111161=111116161111111111111111111116141115.1101111111111111%
...............................................................................
...............................................................................
...............................................................................
...................................
...............................................................................
...............................................................................
...............................................................................
............................................
vleasure, 16 Degree 0.07 0.06 (-0.01, 0.13 0.06 0.06 (-
0.02, 0.39 0.08 0.06 (0.02, 0.
(0.19) 0.20) (0.22) 0.22) (0.15) 0.18)
Standard Deviation, IQR = Interguartile Range
Dxon Signed Rank Sum Test
[Para 108] Table 5 shows the comparisons of interest for the RP dataset. Each
row shows the difference (post- minus pre-treatment) in M(d)/M(uv) ratio or
M(d) measure, at the two degree options. Shown are the statistics for all
eyes,
treated eyes, and untreated eyes. Statistical significance was tested using
Wilcoxon signed rank sum tests due to the small sample size and likely
violation of the normality of these measures. The table shows that M(d)/M(uv)
ratio, 24 degree is significantly higher post-treatment compared to pre-
treatment in all eyes (p=0.04, positive values indicate higher post-treatment
values, negative values indicate higher pre-treatment values) and in treated
eyes (p=0.002). Also, we see that M(d) 24 degree is significantly higher post-
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treatment compared to pre-treatment in treated eyes (p=0.006). The other
comparisons are not statistically significant.
[Para 109] In AMD, AMP average thresholds were improved following SDM
(P=0.0439 ). CVA testing showed significant improvements in VA for all 6
levels
of contrast, from 99% to 35%. (P values from P=0.049 to P=0.006).
[Para 11 0] Table 6. Summary of calculated difference (post- minus pre-
treatment) for eyes with age-related and inherited retinal degenerations
treated
with panmacular SDM retinal protective therapy, Automated Microperimetry
(AMP) eyes accounting for possible inter-eye correlation.
Reduced Threshold 2.72 (16.98) 0.00 (-6.75,
6.75) 0.8487
(Nmiss-8)
P1 ¨4.85 (33.30) 0.50 (-12.00, 0.4664
7.50)
gpZmmmmmmmmmmmmmmFCqQSIZLQ4)mmmma0.0iU5aCta0.0)EM9049mmmmgg
[Para 1 1 1 ] Table 6 shows the comparisons of interest for the AMP dataset.
Each row shows the difference (follow up- minus pre-operation) in reduced and
average threshold as well as P1 and P2. In order to test whether the mean
difference is different from zero, a linear mixed models predicting the
measure,
using an indicator for time (pre-op versus follow-up) as a covariate, also
adjusting for left or right eye, and including a random patient intercept was
performed. The p-values are those associated with the time (pre-op versus
follow-up) regression coefficient. A significant p-value indicates that the
mean
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difference is significantly different from zero. Only average threshold is
significantly different pre-op versus follow-up.
[Para 112] Table 7. Summary of calculated difference (post- minus pre-
treatment), visual acuity on LogMAR scale measured by the Central Visual
Acuity Analyzer in eyes with age-related and inherited retinal degeneration
treated with panmacular SDM retinal protective therapy.
Variable N Mean (SD) Med an (IQR)
99% Contrast 73 -0.146 -0.073 (-0.336, 0.02
(0.511) 0.114)
75%Contast 73 -O 148 -0 058 (-0 30L 001
65% Contrast 73 -0.151 -0.109 (-0.301, 0.006
(0.458) 0.067)
53%Contast 73 -0 107 -0 032 fg0n248irli1040
(0444) 0097)
43% Contrast 73 -0.103 0.000 (-0.250, 0.02
(0.370) 0.058)
35%Contras 73 -Q 104 0 044 (-0 248, 003
[Para 113] Table 7 shows the difference (post- minus pre-treatment) for each
contrast level. In order to test whether the mean difference is different from
zero, linear mixed models predicting the visual acuity, using an indicator for
time as a covariate, also adjusting for left or right eye, and including a
random
patient intercept were used. The table shows significant improvement at all
contrast levels. This method accounts for inter-eye correlation.
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[Para 11 4] Linear regression analyses revealed significant negative
correlations for all testing measures in both AMD and IRD, indicating that the
worse the preoperative measure, the greater the likelihood of postoperative
improvement.
[Para 11 5] 28/33 eyes improved by PERG at one-month post SDM remained
improved by PERG at 6-9 months post SDM. It is possible that other testing
means and measures may be implemented to confirm the beneficial effects of
the invention. For example, Raman Spectroscopy could be potentially used as a
real-time treatment monitoring method. Other testing procedures, including
hyperspectroscopy and reflectometry could possibly used as well.
[Para 11 6] Retinal protective therapy, in accordance with the present
invention, followed by timely functionally-guided retreatment has the
potential
to slow disease progression and reduce complications and visual loss over
time.
For example, it has been found that the invention as a prophylaxis, panretinal
SDM was found to reduce the rate of progression of severe non-proliferative to
proliferative diabetic retinopathy from the expected 50% per year to just
8.5%.
[Para 11 7] Although several embodiments have been described in detail for
purposes of illustration, various modifications may be made without departing
from the scope and spirit of the invention. Accordingly, the invention is not
to
be limited, except as by the appended claims.
