Patent Grant
10952899
The present invention generally relates to a process for safely providing retinal phototherapy. More particularly, the present invention is directed to a process for safely providing retinal phototherapy by adjusting treatment parameters of the retinal phototherapy based on retinal pigment epithelium (RPE) melanin levels determined, such as using a simple reflectometry process.
The importance of macular pigment to the health of the eye has prompted development and interest in methods for measuring its density or concentration in the retina. Prior systems and methods, however, have either been based upon equipment which is not commonly available, is time consuming, or complicated and expensive.
With reference now to
Many diseases of the eye are related to the retina and there have been developed methodologies including photocoagulation and photostimulation of the retina to treat such diseases and conditions. Photocoagulation and photostimulation rely upon heating of the retinal tissue to create their therapeutic effects. Excessive heating can damage or even destroy retinal tissue, which in some treatment methodologies is intentional but in others is avoided. It has been found that abnormal levels of pigmentation, particularly levels or concentrations of melanin within the RPE, can cause unanticipated and excessive heat during such treatments and potentially damage the retinal tissue.
Melanin in the eye has many important functions which are not yet completely understood. Melanin in the eye provides protection to the eye by absorbing harmful ultraviolet radiation. Melanin promotes visual acuity by scattering stray light away from the rods and cones and absorbing light reflected from the back of the eye. Melanin also serves as an antioxidant to aid in the prevention of retinal diseases, such as age-related macular degeneration.
Many of these properties result from the fact that the absorption spectrum of melanin is very broad. In this respect, it is unique among pigments. Many mechanisms have been suggested for this unique behavior. As examples, the broadband absorption has been attributed to chemical heterogeneity, amorphous semiconducting, and scattering. However, it has been shown that scattering losses only account for a few percent of the broadband attenuation. There are also problems with the chemical heterogeneity and amorphous semiconducting hypothesis. Some have proposed polymeric charge hopping. Others have pointed out the importance of hydration and introducing free radicals into melanin. Yet others have suggested that melanin excitons may play a role in its broadband absorption. There does not appear to be universal agreement that any particular explanation can account for all of melanin's electrical and optical properties.
As indicated above, melanin within the eye serves many important functions. The determination of the levels or concentrations of melanin within the eye can be important to ascertain. For example, laser treatments of eye diseases are based on inducing temperature rises in the RPE, which activates the eye's natural repair mechanisms. In the near infrared, this results from the absorption of the infrared radiation by the melanin pigment in the RPE. Considerable melanin also exists in the choroid behind the RPE, but absorption by the choroidal melanin does not play a significant role in raising the temperature of the RPE due to the lack of diffusive heat transfer to the RPE during the relatively short treatment times and due to the convective cooling by the blood vessels in the choroid and the choriocapillaris.
In laser subthreshold damage treatments of eye diseases, the laser treatment is effective as long as the temperature rise does not exceed the order of 10° C. This temperature rise limitation determines the maximum laser energy that can be absorbed by the RPE during the treatment time. A possible concern, however, is that for laser powers that are suitable for most patients, the temperature rise can exceed the threshold for damage if the patient's RPE melanin content or concentration is abnormally too large.
Accordingly, there is a continuing need for a simple and relatively inexpensive process for determining melanin levels or concentrations within the eye, and particularly within the RPE of the eye, so that one or more treatment parameters of the retinal phototherapy treatment can be adjusted as needed to avoid damaging patient's eyes who have an abnormally large content or concentration of melanin in the RPE. The present invention fulfills these needs, and provides other related advantages.
The present invention is directed to a process for safely providing retinal phototherapy by adjusting one or more treatment parameters of the retinal phototherapy if the content or concentration of melanin in the RPE of the eye exceeds a predetermined amount. The present invention uses a two-wavelength reflectometry process for determining the levels or concentrations of melanin in the RPE and choroid of the eye, which is relatively simple and inexpensive.
In accordance with the present invention, a first light beam having a wavelength between 550 nm and 900 nm is generated. The first light beam may have a wavelength of between 600 nm and 850 nm. The first light beam is applied into the eye, such as being applied to a retinal pigment epithelium (RPE) and a choroid of the eye. The amount of light reflected from the eye from the first light beam is measured. This may be done by using a reflectometer to measure the amount of light reflected from the eye from the first light beam.
A second light beam having a wavelength between 550 nm and 900 nm is generated. The second light beam may have a wavelength between 600 nm and 850 nm. The second light beam is of a different wavelength than the first light beam. The first and second light beams preferably differ in wavelength by at least 25 nm. The second light beam is applied into the eye, such as to the RPE and choroid of the eye. The amount of light reflected from the eye from the second light beam is measured, such as using a reflectometer.
The level of melanin within the eye is calculated using the measured amount of light reflected from the eye from the first and second light beams. More particularly, the calculating step includes the step of distinguishing the amount of light reflected by the first and second light beams from the RPE and the choroid.
One or more treatment parameters of the retinal phototherapy is adjusted if the content or concentration of melanin in the RPE of the eye exceeds a predetermined amount. This can comprise adjusting at least one of a retinal spot size of a treatment light beam, a pulse train duration of the treatment light beam, a duty cycle of the treatment light beam, or a power of the treatment light beam. For example, a retinal spot size of the treatment light beam may be increased. A pulse train duration of the treatment light beam may be lowered. A duty cycle of the treatment light beam may be lowered. A power of the treatment light beam may be lowered.
The one or more treatment parameters are adjusted when the content of melanin in the RPE of the eye is determined to be at least four times greater than a normal content of melanin in the RPE. For example, if the content of the melanin in the RPE is determined to be four to eight times a normal melanin content of the RPE, for pulse train durations of the pulsed light beam retina therapy ranging from 0.2 to 0.5 seconds, one or more treatment parameters are adjusted. For example, the one or more treatment parameters are adjusted when the content of the melanin in the RPE is determined to be greater than 8×1010 cm−3.
The one or more treatment parameters of the retina therapy system may be automatically adjusted when the content of the melanin in the RPE of the eye exceeds the predetermined amount. A notification may be given that one or more retinal treatment parameters have been adjusted.
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.
The accompanying drawings illustrate the invention. In such drawings:
For purposes of illustration, the present invention is directed to a process for safely providing retinal phototherapy by determining concentrations of melanin within an eye, and particularly within the retinal pigment epithelium (RPE) and choroid of the eye. Determining the concentrations or levels of melanin within the RPE and choroid of the eye can be important in determining the health of the eye. For example, melanin functions as an antioxidant to aid in the prevention of retinal diseases, such as age-related macular degeneration. Determining the concentrations of melanin within the RPE or choroid of the eye can also be important in determining treatment of eye diseases. For example, if an individual has abnormally elevated concentrations or levels of melanin within the RPE this can cause unanticipated elevated heating, and thus tissue destruction, when treating the eye, and particularly the retina, with light sources, such as infrared or near infrared laser light beams, such as those used in retinal phototherapy, such as photocoagulation or photostimulation.
The melanin layers within the choroid can vary significantly. However, it is the level or concentrations of melanin within the RPE that is often important to determine as this is the layer which can cause excessive heating and damage when the retina is exposed to light sources during photocoagulation or photostimulation treatments. The invention takes into account the light absorbed and scattered by both the RPE and choroid layers in order to get an accurate picture of the amount of melanin in the RPE. The invention, as will be more fully described herein, utilizes two wavelengths within a predetermined range of wavelengths in which melanin both absorbs and reflects these wavelengths. The wavelengths are distinct from one another, preferably towards the lower end and the upper end of the predetermined wavelength range, and the present invention measures the amount or degree of reflections and then determines the levels or concentrations of melanin within the RPE and choroid by taking into account both the absorption and the scattering or reflections of the two wavelengths.
With reference now to
The generated light beam is then passed through optics 106, which may be used to focus the light beam, filter the light beam, generate a plurality of light beams from the generated first light beam, or the like. The light beam is then passed through projector 108, which may be a retina camera or the like, for projection into the eye 10, and more particularly so as to apply the first light beam to the RPE 24 and choroid 26 of the eye 10. Reflections from the RPE and choroid are detected by detector 110. The detector 110 in a particularly preferred embodiment is a reflectometer although other detector devices could be utilized such as those using interferometry such as an Optical Coherent Tomography (OCT) device.
With continuing reference to
The second light beam may pass through optics 106, as described above, and then through projector 108 into the eye 10, and particularly the RPE and choroid 24 and 26 of the eye 10. The light scattered and reflected by the second light beam is detected and measured by detector 110. It will be understood that the first and second light beams generated by consoles 102 and 104 can be applied to the eye 10 sequentially or simultaneously.
The amount of light reflected from the RPE and the choroid by the first and second light beams is measured, and then a concentration of melanin within the RPE and choroid of the eye is determined using the measured amount of light reflected from the RPE and the choroid from the first and second light beams. The invention distinguishes the amount of light reflected by the first and second light beams from the RPE and the choroid and the measurements of the amount of light reflected from the first and second light beams may be applied to calculations and/or graphs or tables to determine the levels or concentrations of melanin within the choroid and more particularly the RPE. The determined level or concentration of melanin within the RPE can then be compared to anticipated or average levels of melanin within the RPE to determine if the melanin levels within the RPE of that eye are elevated or outside of the anticipated range.
The melanin in the eye is primarily eumelanin, and its monomer has the chemical formula C18H10N2O4, and a molecular weight of 318.283, with a density of 1.7 g/cc and an index of refraction of 1.772. In both the RPE and the choroid, melanin is contained in protein-coded organelles, called melanosomes. Inside the melanosomes, the melanin monomers, which have dimensions of less than ten Angstroms, combine to form aggregates. The aggregates have dimensions of several tens of Angstroms, and are made up of stacked sheets of covalently-bonded monomer, with the sheets having separations of 3.4 Angstroms. The sheets are held together by weaker pi-pi bonding forces.
The melanin in the RPE is derived from the neural ectoderm, whereas the choroidal melanin is derived from the neural crest. The melanosomes in the RPE are different from those in the choroid. In the RPE, the melanosomes are located mainly in the apical region of the RPE cells and are elongated in shape, with the long dimension aligned with the apices in order to make close contact with the rods and cones. Typical widths of all foreign RPE melanosome are 250-500 nm, and typical lengths are 640-800 nm. These give 6.5×10−14 cubic centimeters for a typical melanosome volume. The melanin is rather densely packed in the RPE melanosomes, the melanin density in a monomer being 1.7 g/cc.
In the choroid, the melanosomes do not need to be elongated and are believed to be globular in shape. The density of melanin in the choroid is less than that in the RPE, with ranges of 3.61-8.05 mmol/L for RPE melanin, and 0.07-9.15 mmol/L for choroidal melanin. However, since the choroid depth is 200 microns compared to 6-10 microns for the REP, there is much more melanin in the choroid than in the RPE.
In the RPE, from the foregoing numbers, the number density of melanin is 3.38×1018 cm−3 with a mass density of 1.8×10−3 g/cc, and since the melanin is all contained within melanosomes, the corresponding number density of melanosomes in the RPE is 10×1010 cm−3. This gives a linear separation between melanosomes in the RPE of 3.68 microns. In the choroid, on the other hand, the density of melanin is 0.49×10−3 g/cc, corresponding to a melanosome number density of 5.4×109 cm−3. Thus, in the choroid, the linear spacing between the melanosomes is 5.7×10−4 cm, or 5.7 microns.
With reference now to
Prior modeling of the spectral reflectance of the human eye used values of 3.61-8.05 mmol/L for RPE melanin and values of 0.07-9.15 mmol/L for choroidal melanin. The thickness of the melanin layer in the RPE is less than 10 microns, typically around 6 microns, whereas the choroid thickness is on the order of 200 microns, or approximately 30 times thicker. Thus, much more melanin usually exists in the choroid than in the RPE. Moreover, it has been found that the melanin content in the RPE does not usually vary much from patient to patient, although the choroid melanin can vary widely.
As seen in
Transmission=exp[−2αL]=exp[−22.72 exp[−0.0062λ(nm)]] [1]
On the other hand, if an optical density of 0.29 at 500 nm is used, then the result yields:
Transmission=exp[−2αL]=exp[−29.973 exp[−0.0062λ(nm)]] [2]
Equations [1] and [2] are plotted in
By contrast, the optical path in the melanin in the choroid is larger. It has been estimated that the typical density of melanin in the RPE is 5.82 mmol/L, and since the molecular weight of melanin monomer is 318.283, a weight density of 1.86×10−3g/cc is given. This occupies a region of thickness of 6-10 microns. For the choroid, a typical density of 1.59 mmol/L, i.e. 0.51×10−3g/cc, but the thickness of the choroid is 200 microns. Thus, if the optical density of the RPE melanin is 0.22 at 500 nm, the choroid melanin has an optical density at 500 nm of 2.00. Thus, one-way transmission from the back to the front of the choroid is only exp[−2.303×2.00]=0.01. Thus, most of the radiation is absorbed. This means that the reflection from the sclera does not contribute appreciably to the reflection signal. However, there is considerable variation in the choroid melanin content in different eyes and patients, so it is important in general to take account of the contribution of a reflection from the sclera.
Melanin is densely packed in the melanosomes. As described above, in the RPE the melanosomes are elongated in shape and make close contact with the rods and cones. In the choroid, on the other hand, the melanosomes are believed to be globular in shape. The melanosomes are regarded as the basic scattering entities. The melanosomes have dimensions comparable to the 600 nm-850 nm wavelengths of interest. A typical RPE melanosome has dimensions of 250-400 nm (average 300 nm) wide by 640 nm-800 nm (average 720 nm) long. It is assumed that a globular choroid melanosome has a comparable volume to an RPE melanosome, so as to have a radius of 2.5×10−5 cm, i.e. 250 nm.
For dielectric spherical scatterers, when the radiation wavelength is much larger than the size of the scatter, the cross-section for the scattering may be given by the Rayleigh expression:
σRayleigh=(8π/3)(ka)4a2{(Krel−1)/(Krel+2)}2 [3a]
Whereas when the wavelength is comparable to the size of the scatterer, the cross section is expressed in terms of the Mie sum over an infinite series of Legendre polynomials. At small wavelengths, the Mie expression for the total scattering cross section reduces to the asymptotic value:
σsphere=2πa2 [3b]
In eqs. [3a] and [3b], the wave number k is:
k=2πnmed/λ [3c]
and
When ka=O(1), the cross section oscillates a little as it approaches its asymptotic value of σsphere=2πa2.
Another important difference in the behavior of the scattering at long and short wavelengths is that at long wavelengths, there are approximately as many scattering events in the forward as in the backward direction. At short wavelengths, however, this changes dramatically when ka>1, the scattering is predominantly in the forward direction. The scattering angles are contained mainly in a cone of angle:
ϑ=O(1/ka) [4]
Thus, on applying the Born approximation to a spherical scatterer of radius a, it can be shown that:
<cos ϑ>=g[2kasinϑ] [5a]
where
g(x)=(sin x−x cos x)2/x6 [5b]
When ka>>1, this reduces to:
<cos ϑ>=1−(5/4)(1/(ka))2 [5c]
showing that at short wavelengths, the scattering angle is very small.
The cross section σs for a sphere to scatter in backward directions when ka>>1 is then:
σs SPHERE=2πa2[1−<cos ϑ>]=2πa2(5/4)(1/(ka))2=(5/8π)λ2=0.08λ2 [5d]
in the Born approximation, independent of its radius, and just proportional to the square of the wavelength. Since eq. [5d] is derived using the Born approximation, the 0.08 coefficient may not be correct, but the dependence on λ2 is believable since it results from diffraction on a sphere of radius a. [Para 77] The melanosomes in the RPE are not spherical in shape, but are elongated with their long dimensions oriented parallel to the axes of the rods and cones. The melanosomes are comprised of melanin aggregates made up of stacked sheets of covalently bonded melanin monomers.
With reference to
In
The differential cross section for scattering is proportional to the intensity function of the ordinate in the figure. Accordingly, measurement of the areas under the dashed curve and under the solid curve of the sphere of equal volume (labeled “2”) in the figure reveals that the cross section for forward scattering (0 to 90 degrees) in the prolate spheroid is 1.45 times that for forward scattering from a sphere of equal volume. Also, the cross section for backwards scattering (90-180 degrees) in the prolate spheroid is 0.6 that for backwards scattering from a sphere of equal volume. That means that a choroidal melanosome is 1.65 times more effective than an RPE melanosome in scattering radiation in the backwards direction. For the sphere, the ratio of the backwards scattering cross section to the total scattering cross section is 0.018, i.e. only 1.8% of the scattered radiation is in the backwards direction. This is consistent with our earlier observation that most of the radiation is scattered in a small cone about the forward direction (eq. [4]).
Taking the total scattering cross section of the sphere to be 2πa2 (eq. [3b]), the last observation allows us to say that the sphere's cross section for backwards scattering is:
σs(sphere)=0.018×2π2=0.018×2πx(2.5×10−5)2=0.707×10−10 cm2 [6]
at a wavelength corresponding to kc=5.
To determine the wavelength for which eq. [6] applies, examine the expression for kc=5:
Kc=ka[1−(b/a)2]1/2=5 [7a]
i.e.
(2π/λ)360[1−0.25]1/2=5 [7b]
This gives λ=39 nm. Accordingly, since eq. [5d] indicates that the backwards scattering cross section should be proportional to λ2, we find for a general wavelength less than 2πa=1571 nm,
σsCH≈0.43×10−10(λnm/392)232 0.05λ2 cm2 [8a]
This is a little smaller than the 0.08 λ2 cm2 Born approximation result of eq. [5d]. From the measured 0.6 ratio of the backwards scattering cross sections of prolate spheroids and spheres of the same volume in
σsRPE≈0.03λ2 cm2 [8b]
When λ is expressed in terms of nm, eqs. [8] and [9] become:
σsCH≈0.03×10−14λnm2cm2 [9a]
σsRPE≈≈0.05×10−14λnm2cm2 [9b]
Although the absorption is dominated by the melanin in the 600 nm-800 nm range of wavelengths, scattering can also result from the structural matrix in which the melanosomes are embedded. Prior research has determined the scattering properties of the retina and the choroid from OCT scans. For a wavelength of 855 nm:
Retina:
Choroid:
With the large anisotropic factor, the backwards scattering coefficient is obtained from the scattering coefficient by multiplying it by (1-g).
The scattering occurs due to mismatches in refractive index of the different tissue components, ranging from cell membranes to whole cells. Cell nuclei and mitochondria are the most important scatterers. Their dimensions range from 100 nm to 6 μm, and thus fall within the NIR window. Most of these organelles fall in the Mie region, and exhibit highly anisotropic forward-directed scattering.
As the above only gives a scattering coefficient anisotropic factor for the entire retina, and not for the RPE layer that forms the back layer of the retina individually, the RPE scattering coefficient and an anisotropic factor is approximated by using the total retinal quantities. As the scattering coefficient is only given at a single wavelength and since the scattering has been determined as being primarily in the Mie region,
We shall apply the λ2 factor of eq.[5.9] to determine the scattering coefficients at other wavelengths:
μbackscatRET=(1−0.97)120(λnm/855)2=4.92×10−6λnm2cm−1 [10a]
μbackscatCH=(1−0.90)275(λnm/855)2=3.76×10−5λnm2cm−1 [10b]
These can be compared with the scattering coefficients from melanin for normal melanosome densities (NRPE=2×1010 cm−3 and NCH=5.4×109 cm−3)
μsRPE=2×1010×0.05×10−14λnm2=1×10−5λnm2cm−1[normal RPE melanin density] [11a]
μsCH=5.4×109×0.03×10−14λnm2=1.62×10−6cm−1[normal choroid melanin density] [11b]
We see that scattering from the structural matrix in the RPE is less than that from the melanin, whereas in the choroid the scattering from the structural matrix is larger by an order of magnitude.
The scattering coefficients are smaller than the coefficients of absorption at normal melanin densities
μaRPE=2×1010×9.47×10−7 exp[−0.0062λnm]=1.89×104 exp[−0.0062λnm] [12a]
μaCH=5.4×109×9.47 ×10−7 exp[−0.0062λnm]=5.11×103 exp[−0.0062λnm] [12a]
The melanosome number densities and scattering cross sections indicate that not much scattering occurs in traversing either the RPE or the choroid for radiation with wavelengths in the 600-800 nm range of wavelengths. For the 200 micron thick choroid, the typical melanosome density is 5.4×109 cm−3, and with a back scattering coefficient equal to the sum of eqs. [10b] and [11b], this gives an effective mean free path for scattering of an 800 nm photon:
Λmfp=1/25=0.04cm, i.e. 400 microns [12]
This is larger than the thickness of the choroid. The optical density for scattering in the choroid is:
ODscattering in choroid=μscatLCH=(200/400)(1/2.303)=0.22 ([13]
This is much less than the optical density for absorption by the melanin. The scattering optical density in the anterior retina is also small.
In the RPE with a normal melanosome density of 2×1010 cm−3, the mean free path given by eqs. [10a] and [11a] is:
Λmfp=1/9.54=0.0.1cm, i.e. 1000 microns [14]
This is much larger than the 6-10 micron thickness of the RPE, so the probability that a photon is scattered on traversing the RPE is very small indeed. The optical density for scattering in the RPE is:
ODscattering in RPE=μscatw=9.54×0.0006/2.303=0.004 [15]
As in the choroid, this is quite a bit less than the optical density for absorption by the melanin.
Accordingly, in the 600-850 nm range of wavelengths, absorption is more important than scattering both in the RPE and choroid. This then leads to the simple photon transport equations.
We use the simple Kubelka-Munk equations here in order to develop a simple intuition for the dependence of the reflectometry results on the relevant parameters.
Consider first the RPE. The approximate transport equations in the steady state are:
dl(+)/dx=−[N(σs+σa)+μback scat]I(+)+[Nσs+μback scat]I(−) [16]
dl(−)/dy=−[N(σs+σa)+μback scat]I(−)+[Nσs+μback scat]I(−) [17]
Here,
It has previously been demonstrated experimentally that σa/9σs+σa) is quite large, scattering contributing less than 6% to the total optical attenuation across all wavelengths in the UV and optical range.
The quantity N(σs+σa) w is simply 2.303 x the total attenuation (absorption plus scattering) optical density of the RPE melanin layer.
Equations [16] and [17] can be further simplified by ignoring the term+Nσs I(−) in eq. [16], the rationale for this being that the reflected signal I(−) is much smaller than the input signal I(+). Then, on requiring that:
I(+) at x=0 equals the input intensity Io [18a]
I(−) at x=w equals RCHI(+) at x=w [18b]
where:
The 10 micron thick blood-rich choriocapillaris does not contain any melanin, and can be ignored in the 600 nm-750 nm range of wavelengths.
The equations can be solved directly to give for the reflection coefficient RRPE at x=0
RRPE=I(−)at x=0/Io
={Nσs+μbackscat}RPE/{2N(σs+σa)+μbackscat}RPE
+exp[−2w{N(σs+σa)+μbackscat}RPE][RCH−{Nσs+μbackscat}RPE/{2N(σs+σa)+μbackscat}RPE] [19]
The subscript “RPE” has been added in eq.[19] to indicate that the quantities are for the RPE.
In the same manner, an expression for the reflection coefficient RCH at the RPE/choroid interface can be obtained:
RCH={Nσs+μbackscat}CH/{2N(σs+σa)+μbackscat}CH
+exp[−2dCH{N(σs+σa)+μbackscat}CH][RSC−{Nσs+μbackscat}CH/{2N(σs+σa)+μbackscat}CH] [20]
Finally, the total reflection coefficient (at the front of the retina) is given by the same equations to be:
RTOT=1−(1−RRPE)exp[−2μback scatRETdRET] [21]
where μback scatRET is the backwards scattering coefficient of the retinal structural matrix.
In these expressions,
Insertion of eqs. [19] and [20] into eq. [21] results in the desired overall reflection coefficient.
In the reflectivity, cross-sections for the melanosomes in the RPE and for the melanosomes for the choroid both appear. As indicated above, these melanosomes are quite different. The melanin in the RPE is derived from the neural ectoderm, whereas the choroidal melanin is derived from the neural crest. Melanosomes in the RPE have been found to be different from those in the choroid. In the RPE, the melanosomes are located mainly in the apical region of the RPE cells and are quite elongated in shape, with the long dimension aligned with the apices in order to make close contact with the rods and cones. A typical width for an RPE melanosome has been found to be approximately 300 nm, whereas the typical length is 720 nm. In the choroid, the melanosomes do not need to be elongated and are primarily globular in shape. The differences in the shapes lead to the differences in the cross-sections as noted above. The melanin sheets stack to form the aggregates in a melanosome, and thus the RPE melanosomes are represented as lossy dielectric prolate spheroids. The globular melanosomes of the choroid are represented by lossy spherical dielectrics.
With respect to numerical results for the eye, the wavelength-dependent quantities in the reflection coefficient are summarized below:
From the Structural Matrix:
μbackscatRET=4.92×10−6λnm2 cm−1 [22a]
μbackscatRPE=4.92×10−6λnm2 cm−1 [22b]
μbackscatCH=3.76×10−5λnm2 cm−1 [23]
Melanin Related:
σsRPE=0.03×10−14λnm2 cm2 [24]
σsCH=0.05×10−10λnm2 cm2 [25]
σa=9.47×10−7 exp[−0.0062λnm]cm2 [26]
NRPE=2×1010cm−3 for a normal patient [27a]
NCH=5.4×109cm−3 for a normal patient [27b]
Relevant Dimensions:
w=0.0006 cm [28a]
dCH=0.0200 cm [28b]
It is interesting that eq. [23] for the reflectivity depends on only the five parameter combinations:
{σs/2(σs+σa)}CH
{σs/2(σs+σa)}RPE
exp[−2μbackscatRET)dRET]
exp[−2({N(σs+σa)}RPE+μbackscatRPE)w]
exp[−2{N(σs+σa)}CH+μbackscatCH)dCH]
The fourth (exponential) parameter combination provides the desired sensitive measure of the RPE melanin concentration NRPE.
With reference to
With reference now to
As seen from eqs. [19]-[21], the total reflectivity is determined by the reflectivities of the RPE and of the choroid, i.e. by RRPE and RCH. These are shown in
It should be noted that the RPE melanin concentration varies with lateral position in the eye. It peaks at the center of the macula and then decreases on either side over a range of approximately 5° to a relatively constant value for about 10° on either side, before rising again towards the equator at −20° and +15°. To get consistent results, it is best to operate the detector 110, preferably a reflectometer in accordance with the present invention, in the regions where the concentration is relatively constant, or in other words on the order of approximately 10° away from the center of the macula.
The foregoing figures, including
The use of dual-wavelength reflectometry to determine both the RPE melanosomes density or concentration and the choroid melanosome density or concentration is further illustrated in
The curves in the figures herein have been generated with approximate expressions, so the absolute magnitudes of the reflection coefficient shown (of the order of a few percent) should be taken as estimates of the actual reflection coefficient. The actual value will depend upon the specifics of the detectors optics and geometry. A baseline may be established from a population of normal patients, from which deviations can be established. Thus,
Table 1 below shows the peak laser power that will maintain the Arrhenius integral for HSP activation at a conservative value of unity when the RPE melanin content takes on different values. Peak power for different values of spot radius, train duration, duty cycle and abnormal RPE melanin ratio content is shown. The table assumes a treatment pulsed wavelength at 810 nm.
As shown in Table 1 above, the range of the ratio of abnormal RPE melanin content to normal RPE melanin content has been taken to a range between one and eight. The peak laser power depends on the laser spot radius at the retina, the duration of the micropulse train and the duty cycle. For each of these cases, the ratio of abnormal to normal RPE melanin content has been taken to be one, three, five and eight.
Any abnormal RPE melanin content manifests itself through a change in the absorption coefficient of the RPE to the incoming laser radiation: the absorption coefficient is proportional to the total RPE melanin content. Accordingly, in the table, RPE melanin content is represented by 4 values of the ratio of the absorption coefficient α to the normal absorption coefficient αnormal:
α/αnormal=1, 3, 5, 8.
The effect of melanin content on the peak laser treatment power Psdm depends on the laser's retinal spot radius (R), the duration of the micropulse train (tF), and the duty cycle (dc) of the micropulse train (tF). In the table, examples are given for Psdm (in watts) for all possible combinations of:
R=100 microns, 200 microns
tF=0.2 sec, 0.3 sec, 0.4 sec, and 0.5 sec
dc=2%, 3%, 4%, 5%
for each of the 4 values of the ratio α/αnormal.
The value of λnm shown is the value of the peak power that maintains the Arrhenius integral for heat shock protein (HSP) activation Ωhsp at a (conservative) treatment value of unity:
Ωhsp=1.
And it has been assumed that the treatment laser wavelength is 810 nm—for which αnormal=104 cm−1.
For an arbitrary near-IR wavelength (in nanometers) λnm , the treatment powers in the table should be multiplied by the factor ξ(λnm):
ξ(λnm)=Exp[0.0062(810−λnm)]
i.e.
Psdm(λnm)=Psdmξ(λnm)=Psdm(table value)×Exp[0.0062(810−λnm)].
From the foregoing, it can be seen that Psdm decreases as α/αnormal increases; the values of Psdm are larger the larger the spot radius (R) is; the values of Psdm are larger the smaller the train duration tF is; and the values of Psdm are larger the smaller the duty cycle (dc) is.
As can be seen in
At this critical ratio, damage can be avoided and effective HSP activation can be assured, by changing the treatment parameters from their normal values. For example, for most clinical treatment parameters of interest:
The peak power P can be reduced from its normal value Pnormal to lie in the range
Pnormal/rdamage<P<Pnormal
if the duty cycle and retinal spot radius are left at their normal values.
The duty cycle dc can be reduced from its normal value dcnormal to lie in the range
dcnormal/rdamage<dc<dcnormal
if the laser peak power and retinal spot radius are left at their normal values
The retinal spot radius R can be increased from its normal value Rnormal to lie in the range
Rnormal<R<Rnormalrdamage
if the laser peak power and duty cycle are left at their normal values.
Although a single laser phototherapy parameter may be adjusted, it will be understood that more than one of these parameters can also be adjusted simultaneously. For example, the laser spot radius can be increased in diameter and the power lessened, but not lessened to the extent it would otherwise require if only the power were lessened. Similarly, all of the parameters can be adjusted slightly, such as slightly increasing the retinal spot size for the treatment light beam, lowering the pulse train duration of the treatment light beam, lowering the duty cycle of the treatment light beam, and lowering the power of the treatment light beam such that unity in the Arrhenius integral is achieved in order to avoid damage to the retina and eye of the patient having an abnormally large concentration or amount of melanin in his or her RPE.
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.
This application is a continuation-in-part of U.S. application Ser. No. 15/818,216, filed Nov. 20, 2017.
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| Number | Date | Country | |
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| 20190151151 A1 | May 2019 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 15818216 | Nov 2017 | US |
| Child | 16203970 | US |
