United States Patent [19]
`Flower
`
`US005394199A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,394,199
`Feb. 28, 1995
`
`[54] METHODS AND APPARATUS FOR
`IMPROVED VISUALIZATION OF
`CHOROIDAL BLOOD FLOW AND
`ABERRANT VASCULAR STRUCTURES IN
`THE EYE USING FLUORESCENT DYE
`ANGIOGRAPHY
`[75] Inventor: Robert W. Flower, Hunt Valley, Md.
`[73] Assignee: The Johns Hopkins University,
`Baltimore, Md.
`[21] Appl. No.: 63,343
`[22] Filed:
`May 17,1993
`[51]
`Int. CL*........................... A61B 3/12; A61B 3/14;
`A61B 5/02
`[52] U.S. Cl......................................... 351/206; 351/205;
`351/215; 351/221; 128/633; 128/666; 128/691;
`128/745
`[58] Field of Search ............... 351/200, 205, 211, 216,
`351/221, 245, 206, 215; 128/664, 665, 666, 691,
`745, 633; 606/4
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`3,893,447
`7/1975 Hochheimer et al.................. 351/206
`5,150,292
`9/1992 Hoffmann et al...................... 128/691
`5,225,859
`7/1993 Fleischman .......................... 351/206
`5,247,318
`9/1993 Suzuki................................... 351/206
`
`5,279,298 1/1994 Flower.................................. 128/633
`5,303,709 4/1994 Dreher et al...................... 351/221 X
`Primary Examiner—William L. Sikes
`Assistant Examiner—David R. Parsons
`Attorney, Agent, or Firm—Francis A. Cooch
`[57]
`ABSTRACT
`A method for visualizing the choriocapillaris of the eye
`in a sequence of ICG angiographic images comprising
`subtracting each image in the angiographic sequence
`from a succeeding image. In practice, a modified fundus
`camera is used to provide digitized images which are
`subtracted pixel by pixel. To better visualize aberrant
`vascular structures such as choroidal neovasculariza­
`tion (CNV), a fundus camera is modified with a polariz­
`ing filter in front of the light source and an analyzing
`polarizer in front of the video camera. This results in the
`suppression of unwanted scattered fluorescence to the
`extent that the CNV can be better visualized. To assist
`the surgeon in treating aberrant vascular structures with
`laser photocoagulation therapy, a fundus camera is pro­
`vided with two light sources and two barrier filters
`operating synchronously to produce and pass two dif­
`ferent fluorescences thereby generating precisely super-
`imposable angiographs to aid in aiming the laser.
`
`30 Claims, 7 Drawing Sheets
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`U.S. Patent
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`Feb. 28, 1995
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`Sheet 1 of 7
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`5,394,199
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`VI 0 1 .r
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`ILS. Patent
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`Feb. 28, 1995
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`Sheet 2 of 7
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`5,394,199
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`500
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`Grey level
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`U.S. Patent
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`Feb. 28, 1995
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`Sheet 3 of 7
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`5,394,199
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`Fig. 2 A
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`Fig.2B
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`U.S. Patent
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`Feb. 28, 1995
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`Sheet 5 of 7
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`5,394,199
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`Fig. 4
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`FIG.5B
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`FIG.5A
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`U.S. Patent
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`Sheet 7 of 7
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`5,394,199
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`Fig. 6
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`Fig. 7
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`METHODS AND APPARATUS FOR IMPROVED
`VISUALIZATION OF CHOROIDAL BLOOD FLOW
`AND ABERRANT VASCULAR STRUCTURES IN
`THE EYE USING FLUORESCENT DYE
`ANGIOGRAPHY
`
`BACKGROUND OF THE INVENTION
`There is very little information about the blood flow
`through capillary plexuses which occurs on the time
`scale of the cardiac cycle. In part this is because direct
`visualization of such plexuses usually is technologically
`difficult or impossible, and most blood flow measure­
`ment methodologies require that data be obtained over
`many cardiac cycles. Moreover, when the capillary
`plexuses have complex vascular geometries and are fed
`by many arterioles, the additional problem of sorting-
`out blood flow distributions arises. One example of a
`capillary plexus is that found in the cerebral cortex.
`Another example, of great interest to scientists studying
`the eye, is the choriocapillaris, one of three blood vessel
`layers of the choroid.
`The choroidal circulation of the eye bears a major
`responsibility for maintaining the sensory retina which
`lies above it. A prior art method has made possible
`routine visualization of the entire choroidal circulation,
`that is, all three vessel layers of the choroid can be
`visualized, superimposed one above the other. The in­
`nermost layer, the choriocapillaris, constitutes all of the
`nutritive vessels (i.e., where metabolic exchange with
`the retina takes place) for the choroidal circulation. The
`choriocapillaris layer occupies the plane immediately
`adjacent to the sensory retina.
`Although choroidal angiograms show all of the ves­
`sels of the choroid, information pertaining specifically
`to the choriocapillaris is the most important, and there
`are conflicting views about the organization of the pos­
`terior pole choriocapillaris, particularly concerning
`blood flow through it. The method of extracting infor­
`mation about the choriocapillaris from an indocyanine
`green (ICG) angiogram is therefore an important one to
`the clinician who is interested in evaluating the meta­
`bolic sufficiency and stability of the choroidal circula­
`tion.
`Numerous investigators have used angiography and a
`variety of histological techniques to collect the current
`body of information about the choroidal circulation.
`Although the gross aspects of choroidal angioarchitec-
`ture and blood flow have been amply revealed by inves­
`tigators5 efforts, controversies still exist regarding re­
`gional differences in morphology. Additional contro­
`versies have also arisen regarding details of blood flow
`through this highly complicated vascular network.
`Of particular interest is blood flow through the chori­
`ocapillaris, since, as discussed above, it is in this vascu­
`lar layer that the nutritive function of the choroidal
`circulation takes place. Even though the state of the
`larger choroidal blood vessels must certainly influence
`choriocapillaris blood flow, ultimately it is a precise
`understanding of the choriocapillaris blood flow itself
`that is fundamental to understanding the choroid’s role
`in the pathophysiology of retinal disease.
`High-speed indocyanine green (ICG) dye fluores­
`cence angiography was developed to overcome the
`major problems encountered when attempting to visual­
`ize the rapid choroidal blood flow encountered in so­
`dium fluorescein angiography. ICG angiography uti­
`lizes near-infrared wavelengths which penetrate the
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`retinal pigment epithelium and choroidal pigment with
`relative ease. Whereas fluorescence from the choriocap­
`illaris resulting from intravenously injected sodium
`fluorescein dye (the other standard dye used in ocular
`angiography) appears to arise mainly from extravasated
`dye molecules or those adhering to the vessel walls,
`ICG fluorescence arises from dye molecules bound to
`blood protein in the moving blood volume.
`No doubt scanning laser ophthalmoscope fluorescein
`angiography (which can also utilize ICG dye) and the
`experimental technique of injecting fluorescein encap­
`sulated in lipid vesicles eventually will produce addi­
`tional information about choroidal blood flow; but with
`respect to clinical choroidal angiography, ICG angiog­
`raphy provides the best temporal and spatial resolution,
`making visualization of dye passage through the cho­
`roid possible under normal physiological conditions
`(i.e., without having to artificially slow blood flow by
`such methods as raising intraocular pressure).
`When making intravenous dye injections, however, it
`is difficult to observe the choriocapillaris in individual
`ICG angiogram images due to the much higher levels of
`fluorescence arising from the large diameter underlying
`vessels. Due to this multi-layered organization of the
`choroidal vasculature, observation of the choriocapilla­
`ris with fluorescent dye angiography is best accom­
`plished when a very small volume dye bolus having a
`sharply defined wavefront passes through. For exam­
`ple, following intra-carotid injection of a very small
`ICG dye bolus, ICG angiograms have been produced
`which clearly show the complete cycle of dye passage
`through an individual lobule under normal physiologic
`conditions. (Lobule is a term used to denote the three-
`to six-sided vascular units which form a mosaic pattern
`throughout the choriocapillaris. Each lobule consists of
`a cluster of narrow, tightly meshed capillaries which
`appear to radiate from a central focus at which a feeding
`arteriole enters at the posterior wall of the capillaries.)
`Obviously, progression of a sharply defined wave-
`front is more easily tracked through the capillary net­
`work than an ill-defined one. Furthermore, if the bolus
`volume is small enough to essentially clear the underly­
`ing vascular layers by the time it enters the choriocapil­
`laris, then images of the dye-filled capillaries will be of
`higher contrast than when significant fluorescence from
`beneath is simultaneously present.
`Unfortunately, neither of the above conditions is
`readily produced by intravenous injection, even though
`passage of a dye bolus through the choroid can be opti­
`mized by appropriate injection technique. As a conse­
`quence, it is extremely difficult to isolate choriocapilla­
`ris dye filling in raw ICG fluorescence angiograms even
`when they are recorded at high speed. Therefore, there
`is a need for a method that will make it possible to
`extract information about choriocapillaris filling from
`venous-injection ICG dye angiograms.
`Despite their inability to provide complete informa­
`tion about the choriocapillaris, ICG fluorescence angio­
`grams of the choroidal circulation can delineate aber­
`rant vascular structures in the choroid which signifi­
`cantly diminish vision. Age-Related Macular Degenera­
`tion (ARMD) is the leading cause of significant visual
`impairment in the elderly. This disease is frequently
`characterized by development of choroidal neovascu­
`larization (CNV) membranes which invade the sub-reti­
`nal space, resulting in displacement of the sensory re­
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`tina, and often blocking of the visual pathway as a result
`of subsequent hemorrhage.
`Treatment of ARMD is primarily by laser photoco­
`agulation of the neovascular membrane. This treatment,
`however, is successful to the extent that the membrane
`can be accurately mapped; this is because such mem­
`branes are (by definition) in the macular area and often
`encroach on the fovea. Inappropriate application of
`photocoagulation can easily result in destruction of high
`acuity vision, and/or in accelerated growth of the
`CNV.
`Diagnosis of and treatment of ARMD rely heavily
`upon interpretation of angiograms (both fluorescein and
`ICG). Frequently, the morphology of CNV lesions is
`such that the membranes appear in fluorescein angio­
`grams as little more than fuzzy blurs, if at all, especially
`when the membrane lies beneath a cirrus detachment.
`Moreover, today it is recognized that for a class of
`CNV, referred to as “occult-CNV” ICG angiograms
`provide necessary treatment data which sodium fluores­
`cein angiograms cannot.
`A further major difficulty in utilizing ICG angio­
`grams when applying laser photocoagulation therapy is
`that the retinal vascular landmarks upon which the
`surgeon must depend when aiming the laser are often
`missing from the ICG angiograms. The usual approach
`to resolving this problem is to make, during a separate
`setting, color photographs of the fundus and sodium
`fluorescein angiograms of the same eye of the patient; it
`is then necessary to attempt to superimpose the choroi­
`dal ICG angiogram and the retinal photograph or reti­
`nal fluorescein angiogram. This technique often fails
`due to the inability to precisely align the eye in exactly
`the same manner during each of the two angiographic
`procedures. Nevertheless, very accurate alignment
`(within as little as 50 microns on the retina) is vital to
`safely apply laser photocoagulation near the fovea and,
`at the same time, assure no significant permanent dam­
`age to the fovea itself.
`Therefore, there exists a need-for new methods and
`devices to permit both better visualization of aberrant
`vascular structures such as CNV and safer and more
`accurate laser photocoagulation to rid the eye of such
`structures and improve vision.
`SUMMARY OF THE INVENTION
`The method of the invention is based on the premises
`that dye-filling of the choriocapillaris is more rapi-
`d—being pulsatile—than dye-filling of the underlying
`larger diameter vessels and that fluorescence from these
`two overlapping layers is additive. The premise regard­
`ing the velocity of blood in the choriocapillaris runs
`contrary to conventional wisdom regarding the rela­
`tionship between blood velocities in parent and daugh­
`ter vessels in most vascular beds.
`In a nutshell, the invention consists of recognizing
`that pixel-by-pixel subtraction of an image from a suc­
`ceeding image in an ICG angiographic sequence of
`images forms a resultant image sequence which shows
`fluorescence arising only from structures where the
`most rapid movement of blood occurs, i.e., in the chori­
`ocapillaris vessels.
`This subtraction enhancement method of the inven­
`tion makes it possible to extract information about cho­
`riocapillaris dye filling by taking advantage of the dif­
`ferences in large vessel and choriocapillaris blood flow
`rates which naturally exist. Instead of distinguishing
`choroidal layers by temporal sequence of dye bolus
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`4
`appearance, it is dye filling rates which serve to separate
`them.
`Implementation of the invention depends only upon
`configuring an existing fundus camera system to have
`sufficient temporal resolution and magnification of fun­
`dus structure. The described method was applied to
`high-speed ICG fluorescence angiograms to emphasize
`information about choriocapillaris hemodynamics.
`In order to better visualize CNV and facilitate treat­
`ment of ARMD, however, the invention consists of a
`modified fundus camera with a polarizing filter in front
`of the excitation light source and an analyzing polarizer
`in front of the video camera. ICG dye fluorescence
`emanating from the fundus of the eye includes a signifi­
`cant component of polarized light, and rotation of the
`analyzer filter results in unwanted fluorescence (i.e.,
`that not associated with vascular structures, but rather
`associated with scattered light) being suppressed to the
`extent that the underlying CNV can be better visual­
`ized. This particular process affects the unprocessed,
`raw angiographic images in that it improves the signal-
`to-noise content of the individual angiographic images;
`subsequently, the subtracted raw images result in a
`clearer resultant image.
`Once the aberrant vascular structure has been visual­
`ized and delineated by the polarization and subtraction
`methods but before laser photocoagulation therapy can
`begin, the surgeon must be assured that she can prop­
`erly aim the laser. The invention further results from the
`usual practice of performing fluorescein angiography
`prior to performing ICG angiography and makes use of
`the fact that the fluorescein dye remains within the
`retinal vasculature for more than one hour.
`The invention utilizes an ICG fundus camera which
`has an integrating sphere coupled to light sources for
`excitation of both ICG and sodium fluorescein dye
`fluorescences and which uses a gatable charge-coupled
`device (CCD) video camera to capture the angio­
`graphic images. Light input to the integrating sphere is
`via two fiber optic cables each connected to one of two
`light sources. One source is laser output at the wave­
`length needed to excite sodium fluorescein dye (480 nm,
`i.e., a frequency-doubled Nd-Yag); it is also recognized
`that a shuttered, filtered incandescent light source can
`be used in place of a frequency-doubled laser. The other
`source is a diode laser output for excitation of ICG dye
`(805 nm).
`As ICG dye transits through the choroidal circula­
`tion, the gated video camera records images of the ICG
`dye by causing the 805 nm laser diode to fire in syn­
`chrony with the video camera. Appropriate program­
`ming of the camera and light sources are configured
`such that at regular intervals (e.g., every eighth image)
`the 480 nm light source is fired and, simultaneously, an
`appropriate change is made in the barrier filter in front
`of the video camera.
`To use the every-eighth-frame example, a barrier
`filter chain is implemented simply by placing a rotating
`disk containing eight filters in front of the video camera.
`This filter wheel turns in synchrony with the camera
`firings such that every eighth frame corresponds to a
`positioning of the sodium fluorescein barrier filter in
`front of the camera. Because the sequence of angio­
`grams is made at high speeds (approximately 15-30
`images/second), eye movements between successive
`images is insignificant, making precise registration of
`images trivial. Thus, the invention provides the ability
`to precisely superimpose the retinal vessel landmarks
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`contained in sodium fluorescein angiograms on the de­
`lineated CNV lesions in the ICG angiograms, as needed
`by the surgeon to accurately focus a laser for treatment.
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1, consisting of FIGS, la and lb, illustrates an
`ICG fluorescence image of layers of ICG-stained blood
`to demonstrate fluorescence additivity and a graph
`produced from the image, respectively.
`FIG. 2, consisting of FIGS. 2a and 2b, illustrates
`schematically the brightness of fluorescent light emitted
`by two different blood vessels at times ti and t2, respec­
`tively.
`FIG. 3, consisting of FIGS. 3a, 3b, 3c and 3d, are, in
`3a and 3b, ICG fluorescence images showing a 50 de­
`gree field of view centered on the macula of a right eye;
`the images were made 1/15 second apart. FIG. 3c is the
`result of subtracting the image of FIG. 3c from the
`image of FIG. 3b, and FIG. 3d is simply an enlargement
`of FIG. 3c.
`FIG. 4 illustrates a fundus camera system modified to
`provide the angiograms seen in FIGS. 3a and 3b.
`FIG. 5, consisting of FIGS. 5a, 5b, 5c and 5d, illus­
`trates four images of a left eye selected from a sequence
`of images produced by the subtraction method of the
`invention.
`FIG. 6 illustrates a fundus camera system modified to
`suppress unwanted fluorescence.
`FIG. 7 illustrates a fundus camera system modified to
`provide superimposed angiograms.
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENT
`Repeated real-time observations have shown that
`during ICG dye transit, after the large choroidal arter­
`ies fill, there is a rapidly pulsating faint and diffuse fluo­
`rescence superimposed over the steady fluorescence of
`the large vessels at the posterior pole. These pulsations
`appear to occur at a greater frequency than the heart
`rate, and they appear less obvious by the time the large
`choroidal veins are filled. Subsequent frame-by-frame
`analysis of the angiograms, however, indicate that the
`greater-than-heart-rate frequency is a perceptual phe­
`nomenon resulting from the out-of-phase pulsatile fill­
`ing of individual lobules, all at near-heart-rate fre­
`quency.
`Unfortunately, not enough is known yet about details
`of choriocapiUaris hemodynamics to account with cer­
`tainty for the observed more rapid fluorescence inten­
`sity changes in the choriocapiUaris than in the larger
`underlying vessels, but the most likely reason is that
`choriocapillaris blood flow velocity is greater than that
`through the underlying choroidal vessels. The inven­
`tion is based on the premises that the fluorescence inten­
`sities of ICG-filled choriocapillaris and underlying ves­
`sels are additive and that there are detectable differ­
`ences in the rates of change of fluorescence intensities
`emanating from the choriocapillaries and the underly­
`ing choroidal vessels as they fill with dye.
`Although the average cross-sectional diameter of the
`choriocapiUaris is much smaller than that of the under­
`lying arterial and venous vessels which feed and drain
`them, it appears that fluorescence from the two vascular
`layers is additive. ICG fluorescence additivity was dem­
`onstrated by creating a stair-step wedge of overlapping
`thin layers of heparinized blood containing ICG dye
`(0.03 mg/m1); each step was formed by a thin layer of
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`the blood sandwiched between two microscope slide
`coverglasses.
`FIG. la shows an ICG fluorescence image of the stair
`steps. The horizontal white line through the center of
`the image indicates the path along which image pixel
`brightness (i.e., grey level) was measured to produce
`the graph in FIG. lb, demonstrating stepwise increase
`in fluorescence as the number of overlapping blood
`layers increased.
`The greater rate of change in dye fluorescence inten­
`sity in choriocapillaries than in the larger underlying
`vessels is shown schematically in FIGS. 2a and 2b. In
`FIG. 2a, the brightness of a large diameter vessel and an
`overlying choriocapillaris vessel (both in cross-section)
`are indicated as vectors, Ia and I c, respectively. The
`fluorescent light emitted by both is detected at time t]
`by a light sensor, S. In FIG. 2b, the status of the same
`two vessels and sensor is shown at later time t2, where
`ATi and Ale are respectively the incremental increases
`in brightness of the two vessels. Therefore, the total
`brightness detected by the sensor at ti is;
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`At time t2, the total brightness detected is:
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`So.=Ia+Ic+AIa+AIc
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`The change in total detected brightness which occurred
`between ti and t2, AS, then is:
`
`AS=Sa—Sti=&lc+&Jc
`
`But since AIa< <AJq AS=A.la­
`
`in other words, the small change in the combined
`brightness of the overlapping capillary and large vessel
`which occurs during a short time interval is virtually all
`attributable to the choriocapillaris vessel. This phenom­
`enon can be demonstrated by the method of the inven­
`tion, i.e., by subtracting, pixel for pixel, an image in a
`high-speed ICG fluorescence angiogram sequence from
`a succeeding image, as demonstrated in FIGS. 3a-d.
`FIGS. 3a and 3b are angiographic images made 1/15
`second apart. FIG. 3c is the result of subtracting those
`two images, and FIG. 3d is simply an enlargement of
`FIG. 3c.
`Note that in the resultant image (FIG. 3c or 3d) lobu­
`lar structures are seen which were not apparent in either
`of the original images (FIG. 3a or 3b). Also, instead of
`the dye-filled retinal arteries seen in the original images,
`only a dye wavefront representing the movement of
`additional dye into the retinal arteries near the disc is
`seen in the resultant image. Of course, the more spa­
`tially well defined the dye bolus, the more dramatic is
`the effect of the invention. Not all intravenously in­
`jected dye boluses produce as dramatic results as were
`achieved in this example, but in each case there is en­
`hancement of the choriocapillaris component of fluores­
`cence. Note, the subtraction method of the invention is
`intended to operate by subtracting the image from any
`succeeding image.
`To test the method of the invention, five normal
`rhesus monkeys between two and three years of age
`were used. For each observation a monkey was immo­
`bilized by intramuscular injection of ketamine hydro­
`chloride (10 to 15 mg/kg), intubated, and then main­
`tained lightly anesthetized with halothane; mydriasis
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`was induced by topical application of 1% tropicmide.
`ICG fluorescence angiography gradually is being
`Small boluses (about 0.05 ml) of ICG dye (12.5 mg/ml)
`used more frequently by both researchers and clinicians
`were injected through a catheter inserted in the greater
`to investigate the choroidal circulation. Clearly, as such
`saphenous vein and immediately followed by a 2.0 ml
`new tools are applied in a variety of new ways to study­
`ing the choroid, old concepts about it and its physiology
`saline flush. Passage of dye through the choroidal vas­
`will be revisited, and some will change or give way to
`culature was detected using a modified Zeiss fundus
`entirely new concepts. Fortunately, some approaches to
`camera and directly digitally recorded by PC-based
`analyzing choroidal angiograms like the subtraction
`video frame-grabbers. At least three angiographic stud­
`ies of the same eye were performed on different days for
`method of the invention described above may be ap­
`plied both in animal and in human clinical research with
`each monkey.
`In the above test, as shown in FIG. 4, the usual fun­
`complete safety, perhaps hastening a better understand­
`dus camera 10 was modified by replacing the xenon
`ing of choroidal blood flow in health and disease.
`flash tube light source with an 805 nm wavelength laser
`ICG fluorescence angiography is used in the diagno­
`diode 12 coupled to the fundus camera’s illumination
`sis and treatment of ARMD; however, as noted above,
`the difficulty arises in attempting to accurately map
`optics 14 via a small integrating sphere 16 whose exit
`port was located at the position normally occupied by
`choroidal neovascularization (CNV). The invention lies
`the flash tube arc. The fundus camera’s usual means for
`in recognizing that fluorescence arising from a dye
`receiving images, i.e., the photographic film camera,
`molecule contains information about the processes that
`was replaced with an infrared sensitive vidicon tube
`take place within the molecule during the time between
`(model 4532URI Ultracon, Burle Industries) 18 (a
`excitation and emission of light by the molecule. More­
`charge-coupled device could be used instead of the
`over, fluorescence of molecules can be affected by the
`vidicon tube), in front of which an 807 nm wavelength
`characteristics of the substances to which the molecule
`cut-on filter 20 was placed to exclude the excitation
`is bound and by the character of the binding which has
`laser light while admitting ICG dye fluorescence light.
`taken place.
`Choroidal dye transit was recorded in thirty-two con­
`For example, in the case of ICG dye in the vascula­
`secutive video angiographic images at a rate of 30 or 15
`ture of an eye containing CNV, the dye may bind with
`frames per second by two digital frame grabbers (model
`greater affinity to neovascular endothelium than to
`2861-60, Data Translation) (not shown) installed in a
`established endothelium. In such a case, fluorescence
`personal computer (Compaq, model 386/25e) (not
`arising from those bound dye molecules may be substan­
`shown).
`tially different from fluorescence associated with ICG
`FIG. 5 summarizes the angiographic findings ob­
`dye molecules which may be bound to other types of
`tained in the above test by applying the image subtrac­
`protein in the cirrus fluid or from ICG fluorescent light
`tion method of the invention. In this example case, each
`simply scattered by the presence of protein molecules
`image in a 15 frames/second ICG angiographic se­
`within the cirrus fluid. In either event, ellipsometry is an
`quence was subtracted from the image immediately
`appropriate tool for improving the visualization of
`following it; the images in FIG. 5 were selected from
`CNV.
`the resulting sequence of subtracted images.
`The invention then, as shown in FIG. 6, is a modified
`Dye first enters the macular area of the choriocapilla-
`fundus camera 22 with a polarizing filter 24 in front of
`ris which lies temporal to and above the points at which
`the excitation light source 26 and an analyzing polarizer
`the short posterior ciliary arteries enter the eye (FIG.
`28 in front of the video camera 30. ICG dye produces a
`5a). A lobular pattern can be seen in the center of the
`high degree of polarized ability, and rotation of the
`angiogram, particularly just nasal to the center; here a
`analyzer filter results in the fluorescence from the cirrus
`cluster of unfilled lobules is shown (arrows). 0.133 sec­
`fluid being suppressed to the extent that the underlying
`onds later (FIG. 5b) the entire central area is completely
`CNV can be better visualized. This particular process
`filled, although two smaller clusters of late-filling lob­
`affects the unprocessed, raw angiographic images in
`ules may be seen superior to the center (arrows). Chori-
`that it improves the signal-to-noise content of the indi­
`ocapillaris filling progresses almost radially from the
`vidual angiographic images; subsequently, the sub­
`macular region. By close inspection of this image, faint
`tracted raw images result in a clearer resultant image.
`loss of fluorescence around lobules can be seen; these
`Once an aberrant vascular structure such as CNV is
`likely correspond to choriocapillaris drainage channels.
`clearly delineated, it can be treated using laser photoco­
`FIG. 5c is 0.200 seconds later than FIG. 5b. It indi­
`agulation therapy; however, as noted above, aiming the
`cates that the radially oriented wave of choriocapillaris
`laser properly requires superimposing an ICG angio­
`dye filling has been completed, and dye distribution at
`gram and a retinal photograph or retinal fluorescein
`the posterior pole region appears fairly uniform. This
`angiogram. The invention results from the usual prac­
`image indicates that the first wave of dye filling is com­
`tice of performing fluorescein angiography prior to
`plete within the center of the macular region, as indi­
`performing ICG angiography making use of the fact
`cated by the appearance of relatively hypo-fluorescent
`that the fluorescein dye remains within the retinal vas­
`areas which were hyper-fluorescent in FIG. 5a.
`culature for quite long periods of time (more than one
`In FIG. 5d, 0.133 seconds later, it appears that the
`hour). Therefore, if one configures an ICG fundus cam­
`first wavefront of dye filling has reached the peripheral
`era in such a way that during the course of obtaining
`region; at this stage, FIG. 5d is nearly a complete re­
`ICG angiograms, a fluorescein angiogram can be ob­
`verse contrast image of FIG. 5a.
`tained (within fractions of a second of obtaining a previ­
`The wavefront of dye filling traveled radially from
`ous and succeeding ICG angiogram), no significant
`the macular region to the periphery of the 30 degree
`movement of the eye can take place. This means that
`field of view in approximately 0.466 seconds. This over­
`the intervening fluorescein angiogram would, by defini­
`all filling pattern was present in each eye observed, and
`tion, precisely register with the ICG angiograms.
`details of the filling patterns were remarkably consistent
`As shown in FIG. 7, the invention utilizes an ICG
`from observation to observation for each subject eye.
`fundus camera 32 which has an integrating sphere 34
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`9
`coupled to light sources for excitation of ICG dye fluo­
`rescence and which uses, as an image receiving means,
`a gatable video camera 36 (preferably CCD) to capture
`the angiographic images. Light input to the integrating
`sphere is via two fiber optic cables 38, 40, each con­
`nected to one of two light sources 42,44; one source 42
`output is at the wavelength needed to excite sodium
`fluorescein dye (480 nm) and the other source 44 output
`for excitation of ICG dye (805 nm).
`As ICG dye transits through the choroidal circula­
`tion, the gated video camera 36 records images of the
`ICG dye by causing the 805 nm laser source 44 to fire in
`synchrony with the video camera 36. Appropriate pro­
`gramming of the camera and light sources are config­
`ured such that at regular intervals (e.g., every eighth
`image) the 480 nm source 42 is fired, and simultaneously
`an appropriate change is made in the barrier filter 46 in
`front of the video camera.
`To use the every-eighth frame example, the barrier
`filter chain is implemented simply by placing a rotating
`disk containing eight filters in front of the video camera.
`This filter wheel turns in synch