U.S. patent application number 10/635421 was filed with the patent office on 2005-03-03 for treatment of age-related macular degeneration.
Invention is credited to Forman, Michael, Lovoi, Paul A., Smith, Peter C..
Application Number | 20050049508 10/635421 |
Document ID | / |
Family ID | 34193545 |
Filed Date | 2005-03-03 |
United States Patent
Application |
20050049508 |
Kind Code |
A1 |
Forman, Michael ; et
al. |
March 3, 2005 |
Treatment of age-related macular degeneration
Abstract
Age-related macular degeneration is treated by radiation
delivered from a miniature x-ray tube inserted via a catheter
around the globe of the eye, to a position behind the macula.
Methods are described for properly locating the catheter and x-ray
tube, using illumination on the catheter and viewing through the
front of the eye, or sensors on the catheter and a scanned beam
shone from the front of the eye. Fluorescent material excited by
x-rays can also be used. Also described are methods and devices for
immobilizing the probe once properly located in the eye, for
standoff of the x-ray tube from the target issue, and for achieving
prescription radiation dose in the choroid while eliminating dose
to adjacent tissues. The x-ray treatment can be enhanced using a
radiosensitizing drug, and can be combined with PDT.
Inventors: |
Forman, Michael; (Los Gatos,
CA) ; Lovoi, Paul A.; (Saratoga, CA) ; Smith,
Peter C.; (Half Moon Bay, CA) |
Correspondence
Address: |
Thomas M. Freiburger
P.O. Box 1026
Tiburon
CA
94920
US
|
Family ID: |
34193545 |
Appl. No.: |
10/635421 |
Filed: |
August 6, 2003 |
Current U.S.
Class: |
600/476 |
Current CPC
Class: |
A61N 5/062 20130101;
A61N 2005/0659 20130101; A61N 5/1001 20130101; A61F 9/0079
20130101; A61N 5/0601 20130101; A61N 2005/1098 20130101; A61N
2005/1022 20130101; A61N 5/1017 20130101; A61N 2005/0651 20130101;
A61B 2090/306 20160201 |
Class at
Publication: |
600/476 |
International
Class: |
A61B 006/00 |
Claims
We claim:
1. A method for treating AMD, comprising: sliding a catheter around
the globe of the eye of a living patient, the catheter containing a
switchable x-ray source capable of directional emission in a distal
end of the catheter, to a position behind the macular region of the
retina, and switching on the x-ray source to emit directed
radiation through the sclera into the choroidal layer.
2. The method of claim 1, further including properly locating the
catheter behind the macular region by activating light sources on
the catheter, and viewing the light sources using an optical
instrument from the front of the eye, the light sources being
visible through the sclera, choroid and retina.
3. The method of claim 2, wherein the light sources at the catheter
comprise optical fibers receiving light from a source of
illumination at a console to which the fibers are connected.
4. The method of claim 3, wherein the optical fibers have angularly
cleaved ends as said light sources at the catheter.
5. The method of claim 3, wherein the optical fibers are polished
and wherein the light sources at the catheter include microprism
reflectors directing light from the optical fibers toward the front
of the eye.
6. The method of claim 1, further including properly locating the
distal end of the catheter behind the macular region by directing a
preselected pattern of light toward the retina from the front of
the eye, and detecting the pattern of light using detectors located
near the distal end of the catheter, in such a way as to indicate a
direction of movement for correction of the catheter's
position.
7. The method of claim 6, wherein the pattern of light comprises
repeated expanding rings of light.
8. The method of claim 6, wherein the pattern of light comprises a
grid of light lines illuminated sequentially.
9. The method of claim 6, wherein the pattern of light comprises a
color gradation pattern, with color indicating location.
10. The method of claim 6, wherein the pattern of light comprises a
moving pattern of light and the method includes temporally sensing
the position of the catheter by reference to the moving
pattern.
11. The method of claim 1, wherein the switchable x-ray source
comprises a miniature x-ray tube emitting isotropic radiation, with
shielding on the tube such that the emission pattern of the tube,
when the catheter is substantially against the exterior of the
sclera, is directed at the choroidal membrane immediately behind
the macular region and essentially not outside the macular
region.
12. The method of claim 1, wherein the switchable x-ray source
comprises a miniature x-ray tube emitting a side-looking
directional radiation.
13. The method of claim 12, wherein the x-ray tube has an angled
anode and target, with the tube being shielded such that the
emission pattern of the tube, when the catheter is substantially
against the exterior of the sclera, is directed at the choroidal
membrane immediately behind the macular region and essentially not
outside the macular region.
14. The method of claim 12, wherein the x-ray tube is shielded to
provide a desired, limited directional radiation toward the choroid
immediately behind the macula.
15. The method of claim 12, further including filtering the
radiation emitted from the x-ray source to harden the x-ray beam,
using one or more filters coated onto the tube, thus reducing
unwanted dose in the sclera.
16. The method of claim 1, further including filtering the
radiation emitted from the x-ray source to harden the x-ray beam,
using one or more filters coated onto the tube, thus reducing
unwanted dose in the sclera.
17. The method of claim 16, wherein the distal end of the probe
includes an adjustable standoff device for standing the x-ray
source off from the sclera after insertion of the catheter, the
x-ray source comprising a miniature x-ray tube, and including the
step of selecting and balancing parameters of standoff distance of
the source from the sclera and voltage applied to the miniature
x-ray tube, to optimize the parameters to achieve a prescription
radiation dose in the choroid and to limit dose in the sclera and
minimize dose in the retina.
18. The method of claim 1, wherein the x-ray source emits energy in
the range of about 10-30 KeV.
19. The method of claim 18, wherein the x-ray source emits
radiation with an energy of about 15 KeV.
20. The method of claim 1, including properly locating the distal
end of the catheter by a protrusion in the surface of the catheter,
near its distal end, and the method including viewing the retina
from the front of the eye as the catheter is inserted, thus
observing a protrusion in the retina caused by the protrusion on
the catheter, until the catheter is properly positioned.
21. The method of claim 20, wherein the protrusion in the surface
of the catheter comprises an inflatable balloon, and the method
including inflating the balloon of the protrusion to a selected
extent after properly locating the distal end of the catheter to
stand the distal end off from the sclera to a desired extent to
improve the surface to depth dose ratio.
22. The method of claim 21, further including at least one
additional inflatable balloon on the catheter, the additional
inflatable balloon, along with said protrusion, serving to help
immobilize the catheter after proper location of the distal end of
the catheter.
23. The method of claim 21, wherein the x-ray source comprises a
miniature x-ray tube, and including the step of selecting the
extent of standoff of the x-ray source from the sclera, and
selecting a voltage for the x-ray source and optimizing the
standoff and the voltage to achieve a prescription dose to target
tissue of the choroid and minimize dose to non-target ocular
tissue.
24. The method of claim 24, further including filtering the
radiation emitted from the x-ray source to harden the x-ray beam,
using one or more filters coated onto the tube, thus reducing
unwanted dose in the sclera.
25. The method of claim 1, wherein the catheter includes a guide
having a non-round elongated internal cavity, the x-ray source
having a complementary shape fitted to the non-round cavity so as
to orient the x-ray tube rotationally within the guide.
26. The method of claim 25, wherein the non-round cross sectional
shape in the guide comprises generally a keyhole shape.
27. The method of claim 1, further including, prior to switching on
the x-ray source, administering to the patient vascularly a
radiosensitizing drug, in an effective amount to sensitize the
cells in the choroidal layer such that a lower dose or x-ray
radiation can be delivered.
28. The method of claim 1, in combination with photodynamic therapy
administered to the eye, including administering a photo-activated
substance vascularly to the patient and then photo-activating the
substance by directing light through the front of the eye to
thereby disrupt CNV vasculature in the choroid layer at the macula,
the x-ray radiation serving to disable rapidly dividing cells of
the CNV vasculature and to assist in the effects of the
photodynamic therapy by preventing a repair response which
naturally follows photodynamic treatment.
29. The method of claim 1, further including properly locating the
catheter behind the macular region by exciting a fluorescent
substance on the catheter with x-ray radiation from the source, and
viewing the fluorescent substance using an optical instrument from
the front of the eye.
30. The method of claim 29, wherein the x-ray source is a miniature
x-ray tube, and the fluorescent substance being on the tube.
31. A method for inserting and correctly locating a therapeutic
probe by insertion peripherally around the globe of the eye, for
therapeutic treatment of the eye, comprising locating the catheter
behind the macular region by activating light sources on the
catheter, and viewing the light sources using an optical instrument
from the front of the eye, the light sources being visible through
the sclera, choroid and retina.
32. The method of claim 31, wherein the light sources at the
catheter comprise optical fibers receiving light from a source of
illumination at a console at two of which the fibers are
connected.
33. The method of claim 32, wherein the optical fibers have
angularly cleared ends as said light sources of the catheter.
34. A method for inserting and correctly locating a therapeutic
probe by insertion preferably around the globe of the eye, for
therapeutic treatment of the eye, comprising locating the distal
end of the catheter behind the macular region by directing a
preselected pattern of light toward the retina from the front of
the eye, and detecting the pattern of light using detectors located
near the distal end of the catheter, in such a way as to indicate a
direction of movement for correction of the catheter's
position.
35. The method of claim 34, wherein the pattern of light comprises
repeated expanding rings of light.
36. The method of claim 34, wherein the pattern of light comprises
a grid of light lines illuminated sequentially.
37. The method of claim 34, wherein the pattern of light comprises
a color gradation pattern, with color indicating location.
38. The method of claim 34, wherein the pattern of light comprises
a moving pattern of light and the method includes temporally
sensing the position of the catheter by reference to the moving
pattern.
39. The method for inserting and correctly locating a therapeutic
probe by insertion peripherally around the globe of the eye, for
therapeutic treatment of the eye, comprising locating the distal
end of the catheter by a protrusion in the surface of the catheter,
near its distal end, and the method including viewing the retina
from the front of the eye as the catheter is inserted, thus
observing a protrusion in the retina caused by the protrusion on
the catheter, until the catheter is properly positioned.
40. A method for treating AMD, comprising: sliding a catheter
around the globe of the eye of a living patient, the catheter
containing a switchable x-ray source capable of directional
emission in a distal end of the catheter, to a position behind the
sclera and not directly behind the macular region of the retina,
and switching on the x-ray source to emit directed radiation
through the sclera into the choroidal layer, in a direction
essentially tangential or chordal relative to the globe of the eye
essentially not passing radiation through the retina.
41. The method of claim 40, further including properly locating the
catheter behind the sclera in proper position aimed at the
choroidal layer by activating light sources on the catheter and
viewing the light sources using an optical instrument from the
front of the eye, the light sources being visible through the
sclera, choroid and retina.
42. The method of claim 41, wherein the light sources at the
catheter comprise optical fibers receiving light from a source of
illumination at a console to which the fibers are connected.
43. The method of claim 40, wherein the x-ray tube is shielded to
provide a desired, limited directional radiation in said tangential
or chordal direction relative to the globe of the eye.
44. The method of claim 43, further including filtering the
radiation emitted from the x-ray source to harden the x-ray beam,
using one or more filters coated onto the tube, thus reducing
unwanted dose in the sclera.
45. The method of claim 40, including properly locating the distal
end of the catheter by a protrusion in the surface of the catheter,
near its distal end, and the method including viewing the retina
from the front of the eye as the catheter is inserted, thus
observing a protrusion in the retina caused by the protrusion on
the catheter, until the catheter is properly positioned.
46. A method for treating an ocular tumor, comprising: sliding a
catheter around the globe of the eye of a living patient, the
catheter containing a switchable x-ray source capable of
directional emission in a distal end of the catheter, to a position
adjacent to the tumor, and switching on the x-ray source to emit
directed radiation to deliver a prescription dose to the tumor.
Description
BACKGROUND OF THE INVENTION
[0001] This invention concerns treatment of wet age-related macular
degeneration (AMD) in the eye, and in particular concerns use of
radiation to treat such macular degeneration, the radiation being
administered from behind the sclera. Treatment of ocular tumors
also forms a part of the invention.
[0002] Wet age-related macular degeneration has been the leading
cause of blindness in the United States, and a leading cause in the
world. It is characterized by the growth of abnormal blood vessels
from the choroidal membrane at the back of the eye, in the macular
area of the retina including the fovea and immediately surrounding
regions. This is called "choroidal neovascularization" (CNV). The
term "wet" refers to the fact that these abnormal blood vessels
leak and damage the macula, causing central vision distortion.
Thus, the highest resolution vision of the patient is severely
compromised or lost.
[0003] Approximately ten percent of AMD cases comprise wet AMD, and
this is the type which can lead to blindness. Dry AMD comprises
approximately ninety percent of AMD cases, but a certain percentage
of these (approximately ten percent) eventually progress to wet
AMD.
[0004] Of wet patients, approximately seventy percent of these
cases are classic wet AMD, while approximately thirty percent are
what is known as occult AMD. In both cases CNV occurs, invading the
choroid and the space above the choroid with proliferating blood
vessels which cause damage. In the case of classic AMD, the new
blood vessels remain essentially intact, while in occult AMD the
blood vessels leak, form a somewhat amorphous mass, and obscure the
ability of a physician to see the vessel through an ophthalmoscope.
Thus, any treatment aimed specifically at these vessels, requiring
visual identification and location of the vessels, fails for occult
AMD.
[0005] There have been several approaches to treatment of wet AMD.
In both photodynamic therapy (PDT) and transpupillary thermal
therapy (TTT) laser beams are used, directed through the front of
the eye. These have had varying degrees of effectiveness, with PDT
generally being the more effective of the two. In PDT, the
treatment consists of a administering photosensitizing dye followed
by laser treatment, which sensitizes the dye to affect the CNV
condition. Results of both TTT and PDT have been less than ideal.
With PDT, based on one study, only 15% of AMD patients would meet
the Macular Photocoagulation Study Group (MPSG) guidelines for
treatment; thus, most AMD patients would not benefit from this
treatment. In addition, the cost for this treatment has been
extremely high and its cost effectiveness is in question.
[0006] It is also noted that although the FDA recommends PDT
treatment of patients with predominantly classic choroidal
neovascular lesions from AMD, in most cases neovascularization
recurred within three months. Thus, patients will probably need
three to four treatments per year for this therapy to be effective,
and the treatment basically preserves vision rather than improves
visual acuity.
[0007] Researchers have discovered that x-ray radiation can be
effective in treating CNV. Radiation has been administered from
external sources, through the temple area, and also via
brachytherapy using "plaques" which support radioisotope pellets,
these plaques being implanted onto the back side of the eye,
against the sclera, by insertion around the exterior of the sclera.
These implanted plaques have been left in position for a prescribed
duration of time, e.g. about 30 hours, or a range of about 18 to 65
hours at 17.6 Gy. Results of one study showed stabilization or
slight improvement in about 45% of treated patients. After a seven
year follow up, no sight-limiting radiation complications were
noted in any patients. Thus, x-ray radiation, particularly
administered by brachytherapy, is known to have some efficacy in
the stabilization and improvement of the CNV condition of macular
degeneration.
[0008] U.S. Pat. No. 6,443,881, issued to Paul Finger, describes
use of these plaques and methods for locating the plaques using
light sources mounted on the plaques.
[0009] External beam treatment is difficult and generally limited
to highly specialized practitioners, with capital cost for
equipment very high. This treatment is difficult for several
reasons, including inability to produce a very small beam specific
to the target, location of the beam precisely on the target,
radiation damage to other structures, including brain tissue, and
avoidance of the optic nerve and radiation retinopathy.
[0010] In addition to other limitations discussed above, the use of
isotopes is not ideal. They are extremely limited as to choices of
specific activity of the isotopes, as well as energy. Further, the
isotopes must be shielded during emplacement for brachytherapy, as
well as shielded directionally to protect adjacent structures,
since the isotopes are isotropic emitters.
[0011] A much improved treatment for CNV of macular degeneration
would be a controllable x-ray source which can be placed
non-surgically adjacent to the macula, with accurate placement,
with reliably accurate directional emission, and which can be
controlled as to depth of radiation penetration as well as dose.
These are objects of the present invention described below.
SUMMARY OF THE INVENTION
[0012] This method is a method and device by which a miniature
x-ray source is inserted around the globe of the eye,
non-surgically, to locate the source directly adjacent to the
macula, behind the eye and against the sclera. The miniature x-ray
tube is switchable off/on as well as controllable, in preferred
embodiments, as to voltage (penetration) and current (dose).
Invention of the source is via a catheter/probe which is inserted
around the globe to the back of the eye and positioned adjacent to
the target tissue. The miniature x-ray tube within the catheter is
on the order of about 1 mm in diameter with a length of
approximately 7 mm (although dimensions can vary). By this device,
a therapeutic dose of ionizing radiation is delivered to the
abnormal vessels in the choroid layer. This therapeutic radiation
tends to seal or close the bleeding vessels through a process that
causes vessel fibrosis. Adjacent tissue cells which are not
actively proliferating are less affected by the radiation, as is
well known.
[0013] An important advantage of delivering ionizing radiation from
the back of the eye is that a therapeutic dose can be given to the
lesion without damaging structures of the eye, i.e. the lens,
retina and optic nerve. The membranes at the back of the eye are
relatively radioresistant.
[0014] The invention encompasses a method and means for accurate
location of the catheter and x-ray tube behind the eye. Several
different guidance techniques can be used. In accordance with one
technique a bump or ridge is provided on the probe or on the guide,
forming a moving mound on the retina, as the device is manipulated,
visible to the physician from the front of the eye. This provides a
fiducial for the physician to accurately locate the anode end of
the x-ray tube. Another approach is using light or invisible
radiation, directed from the front of the eye, as a tool to locate
the probe either spatially or temporally. As one example, a light
emitting device from the front of the eye can generate a series of
expanding rings of light. These can be sensed by a plurality of
sensors on the exterior of the probe, the tissues from the retina
to the back of the sclera being relatively translucent. Even though
the rings of light will be somewhat scattered when reaching these
sensors, their peaks can be detected and this will give enough
information, fed back to the console, to determine which direction
the probe should be moved to effectively center the device and
align the radiation source to the macula.
[0015] Infrared radiation can be used advantageously in location of
the probe. IR can be directed in from the front of the eye,
invisible to the patient and thus not uncomfortable to the patient,
and this radiation will penetrate through the retina, choroid and
sclera to the sensors on the device.
[0016] Another alignment device can have light sources positioned
on the probe itself, as in the Finger patent referenced above. By
the invention these light sources can be cleaved optical fibers or
polished fibers with redirecting reflectors at the fiber ends
(microprisms), with the origin of the light being back in the
console. These fiber ends can serve as "headlights" to locate the
probe by reference to the position of the light sources at they
appear from the front of the eye. Other variations can include
color gradations shone through the front of the eye, a grid of
light patterns, or other devices involving the sensing of light
from either the probe or from the front of the eye. A modified
embodiment to use fluorescence of a material struck by the x-rays
to enable seeing the location of the x-ray beam by looking into the
front of the eye. A fluorescence material could be put into the
blood or the ocular fluid to fluorescence with short bursts of
x-ray radiation to locate the device. Alternatively, the tube
itself can have a fluorescing material, to glow when excited by
x-rays and visually locate the probe.
[0017] With the invention the radiation dose and depth can be
matched to the prescription for the CNV condition, while minimizing
radiation to healthy adjacent structures. Several parameters are
adjustable to achieve this. In addition, the x-ray tube in the
probe preferably is made directional, and an ideal window of
radiation can be provided for the treatment as desired, relative to
the distance of the treatment area and the width of the treatment
area as seen from the x-ray tube.
[0018] Filtration of the x-ray beam from the miniature tube can be
put in place if needed. This can greatly reduce low-energy
emissions (i.e. "hardening" the beam), thus reducing dose in the
near field, i.e. the sclera, where radiation is not desired. This
in combination with standoff of the source after placement and
adjustment of voltage, enable optimizing dose to the choroid,
sclera and retina.
[0019] It is important that the probe be immobilized during
treatment. Several methods can be used. The "bump" on the probe
device described above can be inflatable, thus being inserted
flattened but inflated (with liquid) when near the macula. Further
inflation can help hold the probe against the adjacent tissues (and
also stands the source off from the tissue as described below).
Another inflatable balloon can be at the back side of the probe,
and a further balloon(s) can be located on the catheter proximal to
the x-ray source for further immobilization of the catheter and
probe.
[0020] Another aspect of the invention is that drugs can be used to
enhance the effectiveness of the radiation treatment, thus allowing
lower radiation doses to be administered. Similar to the concept of
PDT described above, radiation-enhancing drugs can be administered
systemically, causing the irradiated regions to be more sensitive
to radiation, but having no effect on the body tissues in
non-irradiated area.
[0021] It is therefore among the objects of the invention to
improve radiation therapy as a treatment for wet exudive macular
degeneration, by use of a probe having a controllable radiation
source which can be accurately located behind the macula for
accurate delivery of the radiation. These and other objects,
advantages and features of the invention will be understood from
the following description of preferred embodiments, considered
along with the drawings.
DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 is a schematic view in sectional plan showing an eye
and a catheter being inserted non-surgically around the globe,
behind the macular region.
[0023] FIG. 2 is an enlarged view in sectional plan showing the
catheter or probe of the invention behind the macular region.
[0024] FIG. 3 is a schematic partial plan view showing an
embodiment of the catheter of the invention having one type of
x-ray source locating means, in this case a protrusion on the
surface of the catheter, which also serves as an immobilizer and a
standoff to improve radiation surface to depth ratio.
[0025] FIG. 3A is a view similar to FIG. 3, showing an inflatable
protrusion on the catheter or probe, and also showing additional
inflatable balloon devices for immobilization.
[0026] FIG. 4 is a schematic view as seen from the front of the eye
and showing the macula and surrounding blood vessels and also
revealing the x-ray source of the invention positioned behind the
macula (which would actually not be visible through the eye), in
this case showing incorrect positioning of the x-ray source.
[0027] FIG. 5 is a view similar to FIG. 4, but showing the x-ray
source correctly positioned behind the macula.
[0028] FIG. 6 is a schematic view showing expanding rings of light
shone in from the front of the eye, as another method and device
for properly locating the x-ray source behind the macula.
[0029] FIG. 7 is a schematic view showing a grid of light lines
which can be sequentially activated and detected from sensors on
the probe or catheter device, as another means and method for
properly locating the x-ray source.
[0030] FIG. 8 is a schematic view indicating light sources mounted
on the catheter or probe device as another alternative for properly
locating the x-ray source behind the macula.
[0031] FIG. 9 is a schematic view showing, in a primarily plan
view, a limited radiation pattern emitted from the x-ray source and
treating the choroid layer behind the macula.
[0032] FIG. 10 is a schematic plan sectional view showing an x-ray
tube for side-looking, directional radiation.
[0033] FIG. 11 is a schematic sectional view showing "keying" of an
x-ray source within a surrounding sheath containing cooling
channels.
[0034] FIG. 12 is a sectional schematic view showing tangential or
chordal radiation with respect to the globe of the eye, from the
x-ray source toward the macula.
[0035] FIG. 13 is a graph of dose versus depth of penetration of
radiation, i.e. a dose profile for one embodiment of the system in
method of the invention.
DESCRIPTION OF PREFERRED EMBODIMENTS
[0036] FIG. 1 of the drawings shows a patient's eye 10, generally
in plan view and cross section, and schematically indicates a probe
or catheter device 12 inserted around the globe of the eye, along
the surface of the sclera 14. The macula, or macular region, is
shown at 16, a region of the retina of the eye. The probe or
catheter device 12, which is shown schematically and may include an
outer sheath or guide within which the catheter is inserted,
includes a switchable x-ray source 20 at its distal end. The source
20 preferably comprises an x-ray tube which emits radiation when
switched on and which optionally can be varied as to current and
voltage, emitting a side-looking directional radiation toward the
macula 16, through the sclera 14 and the choroidal membrane or
layer immediately behind the macula. Accurate positioning of the
x-ray source 20 is an important aspect of the invention and is
discussed below.
[0037] FIG. 2 is an enlarged, detailed view, schematic in its
illustration of the x-ray source 20. The source 20 is immediately
behind the sclera 14, and the source, or the sheath or guide
surrounding the source, directly contacts the back surface of the
sclera. As the drawing schematically indicates, the choroid, or
choroidal layer 22, is the next tissue layer in from the sclera.
The sclera may be about 1 mm in thickness in this region, while the
choroidal layer may be only about 0.5 mm thick. Immediately inside
the choroidal layer is the retina 26.
[0038] The fovea 28 is at the center of the macular region 30,
which is typically considered as a region of about 5 to 6 mm in
diameter around the phobia (including the foveola, fovea,
parafoveal and perifoveal regions). As FIG. 2 indicates, this
region is very close to the optic nerve 32, where radiation is to
be avoided. The choroidal layer 22, as explained above, is the
region where CNV of age related macula degeneration occurs, and
this is the layer, directly behind the macula, to be treated with
x-ray radiation according to the invention.
[0039] FIGS. 3-8 are concerned with properly locating the probe or
catheter 12, and particularly the x-ray radiation, behind the
macula. In FIG. 3 one scheme is illustrated for indicating to the
physician the location of the x-ray tube behind the retina, and
thus allowing adjustment and proper positioning of the probe to
approximately center the tube behind the macula. By this
arrangement the probe 12 containing the x-ray tube 20, i.e. the
exterior of the apparatus inserted around the globe of the eye
(which can be a guide), has a "bump" or protrusion 32. This
protrusion 32 which can be considered as exaggerated in relative
size in FIG. 3, forms a moving ridge or bump in the retina, which
is visible to the physician using an optical instrument from the
front of the eye. As seen in the schematic view of FIG. 3, the bump
32 preferably is centered over the anode of the x-ray tube 20, i.e.
the portion of the tube from which the x-rays 34 originate. In FIG.
3 the end of the probe 12 is shown as round, in atraumatic type
36.
[0040] FIG. 3A shows a variation of what is shown in FIG. 3. In
both FIGS. 3 and 3A, the bump 32 or 32a forms an immobilizing
function as well as the locating function described above. The bump
32, 32a pushes against the sclera and thus tends to wedge the probe
device more tightly between the sclera and adjacent tissue.
Further, this bump 32, 32a serves to stand the radiation source 20
off from the sclera and choroid layers, thus improving surface to
depth ratio for the emitted radiation. In FIG. 3A the bump 32a is
inflatable, via a lumen (not shown) in the catheter 12a, and the
amount of inflation can be varied as needed. This standoff distance
is correlated with the voltage setting for the tube 20, thus
enabling the physician to optimize x-ray radiation dose in the
choroid while minimizing dose in the retina and in the sclera. FIG.
3 also shows an additional inflatable balloon protrusion 33 which
can be located on the opposite side of the probe device from the
radiation side. This balloon 33, also inflatable via a lumen or
duct (not shown) in the catheter 12a, like the bump 32a, is
deflated when the probe is inserted. It can be inflated to a
selected inflation for helping immobilize the probe after the tube
has been properly located behind the macula. Also shown in FIG. 3A
is a third inflatable balloon structure 35 which can be included at
a selected location along the length of the catheter 12a, to
further immobilize the probe and to isolate the catheter tip and
x-ray source from movements of the catheter at the proximal and
after properly locating the probe. Again, the balloon 35 is
deflated during insertion.
[0041] Vacuum, i.e. suction against tissues, can also be used to
immobilize the device after it is properly located. Suction can be
applied through a separate lumen (not shown) in the catheter, and
can be applied via openings on the protrusion 32a or 33, spreading
the suction over a relatively wide area.
[0042] FIGS. 4 and 5 show schematically, relative to the procedure
of properly locating the x-ray tube 20 behind the macula (it
actually would not be visible from the front of the eye). FIG. 4
shows an example of incorrect positioning of the probe. Blood
vessels to the macular region are indicated at 38 in this
drawing.
[0043] FIG. 5 is similar to FIG. 4, but shows the probe 12 and
x-ray tube 20 correctly positioned behind the macula 30. FIGS. 6, 7
and 8 show examples of optical methods and means by which this can
be achieved.
[0044] In FIG. 6 is shown a series of light rings 40, 42, 44 and
46. These are directed in from the front of the eye, centered on
the macular region which is shown at 30 in FIG. 6. The centering of
the rings is done by the physician, using an instrument at the
front of the eye. The light rings, 40, 42, etc. are constantly
expanding (and reappearing at center). Behind the retina is the
probe, with a plurality of sensors 48 (in this case four) mounted
on the device and preferably centered around the x-ray emission
point of origin. These sensors 48 detect the passing of each ring
of light 40, 42, 44 and 46 as it expands. Even though the light
rings will be considerably scattered as they pass through the
partially translucent retina, choroid and sclera to reach the
sensors 48, their peak intensities will be detectable at each point
48. Thus, as the rings expand the timing of each peak detection by
each of the sensor points 48 is fed to a console (not shown)
connected to the probe instrument, and from this information the
location of the sensors relative to the center point of origin of
the light rings can be determined. When centered the detectors 48
will all detect light peaks simultaneously. Thus, an instruction
can be generated to the physician as to what direction the probe
should be moved in order to achieve correct positioning, or the
positions of the probe relative to the macula can actually be
displayed on a screen on or connected to the console. A robotic
device can be used to position the probe, with robotic feedback
from the sensors 48 and console.
[0045] FIG. 7 shows another probe-location method and system. By
this method, a grid of light lines, e.g. vertical light lines 50
and horizontal light lines 52, are generated by an instrument which
directs the light in from the front of the eye. The four sensor
points 48 discussed with respect to FIG. 6 are shown behind the
grid of lines. FIG. 7 is only schematic, and the line spacing in
the grid is sufficiently small that light from at least lone light
line will always be detected by at least some of the plurality of
sensors 48 mounted on the probe device. As discussed above, this
light will be highly scattered after passing through the retina,
choroid and sclera, but its peaks will be detectable. The grid of
lines 50, 52 is located by the physician as accurately as possible
relative to the macula of the eye, as by a special, distinctively
illuminated location intersection 54. The light lines can be
sequentially activated, so that the feedback from the sensors 48
will always identify which line of light was detected and by which
sensor or sensors. This will give enough information to tell the
physician (or a robotic probe manipulator) where the probe is
located, and which direction and how far to move it in order to
make it properly located behind the macula.
[0046] Alternatively, the grid shown in FIG. 7 can represent
scanned light lines moving across the retina (fewer lines are
needed). By temporal synchronization, the location of each light
line at any time is known, allowing the sensors and connected logic
to locate the probe. Note that only two, or even one sensor 48 is
sufficient for this form of scan locator.
[0047] FIG. 8 shows another scheme for properly locating the x-ray
tube 20 behind the macular region 30. This arrangement is somewhat
similar to that of the Finger patent discussed above, in that light
sources 56 are mounted directly on the probe. Four are shown in
FIG. 8. In the invention, however, these light sources are
angularly cleaved optical fiber ends which receive light from an
illumination source in the console. The fiber ends 56 are
sufficiently bright that the physician can see the pattern of these
light sources behind the macula, and can locate the probe
accordingly. The fiber ends may be angularly cleared, or polished
and redirected by reflectors (microprisms).
[0048] Another method for indicating and confirming position of the
x-ray source behind the eye is to provide a means of seeing the
x-ray radiation itself, or seeing evidence of the x-ray radiation,
by looking into the front of the eye. This method could involve
fluorescence, of a casing around the x-ray source, or of a
medically acceptable substance put into the blood stream, which
substance fluoresces when absorbing x-ray radiation. Such a
substance could be injected into the intraocular space.
[0049] Another way of producing a fluorescing indicator is to use
the x-ray tube itself or a transmissive plate or coating on the
x-ray tube, as a substance which will fluoresce when struck by
x-rays. The applicant has found that sintered aluminum nitride will
fluoresce when excited by x-ray radiation.
[0050] The x-ray therapy of the invention can be used in
conjunction with photodynamic therapy, as mentioned above. By using
the two therapies simultaneously (or closely in time to one
another), the disruption caused by PDT can be synergistically
complemented by radiation therapy. PDT essentially causes a
disruption of the capillaries of the choroid layer by a photoactive
chemical substance as explained in U.S. Pat. No. 6,548,542 (col. 4,
1. 61- col. 5, 1. 4), incorporated herein by reference. The
photo-activated substance is thought to break down cellular
structures and other effects as noted in the '542 patent, resulting
in occlusion of the CNV rasculative. X-ray radiation delivered in
conjunction with PDT can help remediate AMD in two ways: first, the
direct effect is to disable rapidly dividing cells, thus reducing
the population of cells which can cause the problem by growing new
inappropriate vessels (CNV), and secondarily, the radiation assists
in the effects of the PDT by preventing the repair response which
naturally follows the PDT treatment.
[0051] The invention also encompasses use of radiosensitizing
substances in the blood vessels to enhance their sensitivity to
radiation. This is the subject of copending application Ser. No.
09/851,372, filed May 7, 2001, assigned to the assignee of the
present invention. That copending application is directed primarily
at a combination of radiation and radiosensitizer delivery devices
to inhibit hyperplasia following balloon angioplasty. The
application discloses radiosensitizers such as taxol, misonidazole,
metronidazole, etanidazole, 5-fluorouracil, texaphyran, C225 (an
anti-EGFR monoclonal antibody), and cyclooxygenase-2 inhibitor. In
the present invention, a radiosensitizer such as one of these
substances is put into the blood in an effective amount to
sensitize the cells in the choroid layer such that a lower dose of
x-ray radiation via the probe of the invention can be
administered.
[0052] FIG. 9 is a simple schematic showing the x-ray source 20 at
the distal end of the catheter or probe 12 and properly located
behind the macular region 30 of the eye. The portion of the
choroidal layer 22 to be irradiated, i.e. the choroid directly
behind the macula, is indicated at 60. The x-ray radiation is shown
in a diverging pattern at 34, emanating from a source (the anode)
62 in the x-ray tube, at the proper angle to irradiate the region
of interest 60 in the choroid. FIG. 9 shows adjacent structures are
irradiated, including the sclera 14 and the retina 26. An
approximate dose to depth curve is shown in FIG. 13. The sclera
necessarily receives more radiation than the other structures, but
the sclera comprises relatively quiescent cells which are not
rapidly proliferating, and the radiation dose is not so excessive
to cause a problem. The next layer is the choroid with the CNV
condition of macular degeneration. This region receives sufficient
radiation to provide therapeutic benefit to the patient. Beyond the
choroid 22 is the retina 26, which receives a still smaller dose.
Regions deeper toward the front of the eye, including the lens and
cornea (not shown), receive progressively less dose. With proper
selection of voltage filtering and stand-off the switchable x-ray
source can deliver considerably less radiation to structures distal
to the target tissue (choroid) than current isotope plaque
treatment. No radiation damage has been seen in patients treated
with plaques with up to 7 years follow-up.
[0053] FIG. 10 schematically indicates an anode construction for
the x-ray tube 20, for achieving side-looking, directional
emission. In this arrangement the anode comprises an angled face
64, i.e. at approximately 45.degree. (from 22.degree. to
60.degree.) to the direction of the approaching electron beam 66,
so that emission is essentially through an arc A. However, the
x-ray tube 20 is shielded, as shown at 68 on the back side and 70
on the front side, so that only a desired window of side-looking
radiation is emitted, through a desired angle B. The arc of
radiation is limited in two dimensions, thus producing radiation
which can be an approximate cone. The geometry of the tube and its
shielding are selected so that, with the distance from the anode to
the choroid layer known, and the width or diameter of the choroid
behind the macula known, the correct angle of radiation is emitted.
Shielding alone can be relied on to produce the side-looking
radiation desired from an x-ray source without an angled anode.
[0054] FIG. 11 is a simplified schematic view showing a "keyed"
arrangement for proper rotational orientation of the x-ray source
within the catheter or an immediately surrounding sheath 72. The
x-ray tube or source 20 has a ridge or protrusion 74, which fits
within a complementary channel 76 within the sheath 72 or probe. In
the case illustrated, the immediately surrounding structure is a
sheath 72 having cooling channels 78, 80, etc. This may be
surrounded by a guide 82 shown in dashed lines, and the sheath 72
itself may be keyed for proper rotational orientation within the
guide 82. A keyhole shape such as illustrated with the tube 20 is
not needed; a simple, small elongated ridge or a shorter bump, or a
non-round shape such as elliptical will suffice to provide
orientation. It is imperative that the side-looking x-ray device be
properly oriented to direct the radiation toward the choroid region
to be treated. This can be achieved by many different
arrangements.
[0055] FIG. 12 shows an alternative method for irradiating the CNV
affected choroid region, shown at 84 in this simple schematic. The
optic nerve 32 is shown in FIG. 12 but is behind the plane of
treatment in which are located the probe 12 and the treatment
region 84. In this case the x-rays 86 are directed generally
tangentially to the eye, or chordally, as illustrated. This is a
method for avoiding any significant radiation to the retina,
indicated at 26, by passing the radiation essentially tangentially
or chordally through the sclera and a part of the choroid, to the
region of CNV directly behind the macula. The x-ray source tailored
to produce a flat beam of the appropriate width and direction.
Distances in FIG. 12 are neither to scale nor proportional.
[0056] The apparatus and method of the invention also can be used
to treat ocular tumors with radiation. The same catheter is used,
with a switchable source having an appropriate direction of
radiation, for tumors at different locations in the ocular
tissue
[0057] The above described preferred embodiments are intended to
illustrate the principles of the invention, but not to limit its
scope. Other embodiments and variations to this preferred
embodiment will be apparent to those skilled in the art and may be
made without departing from the spirit and scope of the invention
as defined in the following claims.
* * * * *