Abstract

A novel technique, Multiply Scattered Light Tomography (MSLT), and confocal Infrared Imaging are used to provide diagnostic information using a comfortable, rapid, and noninvasive method. We investigated these techniques in detecting neovascularization in age-related macular degeneration. The MSLT used a Vertical Cavity Surface Emitting Laser (VCSEL) at 850 nm, while the confocal imaging technique used either the VCSEL or a 790 nm laser diode. Both were implemented into the topographical scanning system (TopSS, Laser Diagnostic Technologies, Inc.) Confocal imaging with both lasers provided different information about neovascularization as a function of focal plane, and different also from MSLT.

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  1. H. Leibowitz, D. E. Kruger, L. R. Maunder, R. C. Milton, M. M. Kini, H, A. Kahn, R. J. Mickerson, J. Pool, T. L. Colton, J. P. Ganley, and J. Loewenstein, "The Framingham Eye Study Monograph: an ophthalmological and epidemilogical study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973-1975," Surv. Ophthalmol. 24, (Suppl) 335-610 (1980).
    [PubMed]
  2. R. H. Webb, GW Hughes, O. Pomerantzeff, "Flying spot TV ophthalmoscope," Appl. Opt. 19 2991-2997 (1980).
    [CrossRef]
  3. R. H. Webb and G. W. Hughes, "Scanning laser ophthalmoscope," IEEE Trans. Biomed. Eng. 28, 488-492 (1981).
    [CrossRef] [PubMed]
  4. A. W. Dreher and R. N. Weinreb, "Accuracy of topographic measurements in a model eye with the laser tomographic scanner," Invest. Ophthalmol. Vis. Sci. 32, 2992-2996 (1991).
    [PubMed]
  5. R. H. Webb, G. W. Hughes, and F. C. Delori, "Confocal scanning laser ophthalmoscope," Appl. Opt. 26, 1492-1499 (1987).
    [CrossRef] [PubMed]
  6. A.W. Dreher, P.C. Tso , and R. N. Weinreb, "Reproducibility of topographic measurements of the normal and glaucomatous optic nerve head with the laser tomographic scanner," Am. J. Ophthalmol. 111, 221-229 (1991).
    [PubMed]
  7. For a review of the early infrared scanning laser techniques, see A. E. Elsner, A. H. Jalkh, A.H, and J. J. Weiter, "New devices in retinal imaging and functional evaluation," in Practical Atlas of Retinal Disease and Therapy, W. Freeman, ed. (Raven, New York, 1993) pp. 19-35. The work of several groups is found in A. E. Elsner, D-U. Bartsch, J. J. Weiter, and M. E. Hartnett, "New devices in retinal imaging and functional evaluation," in Practical Atlas of Retinal Disease and Therapy, W. Freeman, ed. (Lippincott-Raven, New York, 1998) 2nd edition, pp. 19-55.
  8. A. E. Elsner, S.A. Burns, S.A., Kreitz, M.R., and J. J. Weiter, "New views of the retina/RPE complex: quantifying sub-retinal pathology," in Noninvasive Assessment of the Visual System, Vol. 1 of OSA Technical Digest (Optical Society of America, Washington, D.C., 1991, pp. 150-153).
  9. A. E. Elsner, S. A. Burns, G. W. Hughes, G.W., and R. H. Webb, "Reflectometry with a Scanning Laser Ophthalmoscope," Appl. Opt. 31, 3697-3710 (1992).
    [CrossRef] [PubMed]
  10. A. E. Elsner, S. A. Burns, J. J. Weiter, and F. C. Delori, "Infrared imaging of subretinal structures in the human ocular fundus," Vision Res. 36, 191-205 (1996).
    [CrossRef] [PubMed]
  11. A. E. Elsner, A. W. Dreher, Q. Zhou, E. Beausencourt, S. A. Burns, R. H. Webb, "Multiply scattered light tomography: vertical cavity surface emitting laser array used for imaging subretinal subretinal structures," Lasers and Light in Ophthalmology 8, 193-202 (1998).
  12. F. C. Delori, "Spectrophotometer for noninvasive measurement of intrinsic fluorescence and reflectance of the ocular fundus," Appl. Opt. 33, 7439-7452 (1994).
    [CrossRef] [PubMed]
  13. L. M. Kelley, J. P. Walker, G. L. Wing, P. A. Raskauskas, and A. E. Elsner, "Scanning laser ophthalmoscope imaging of age related macular degeneration and neoplasms," J. Ophthalmic Photography 3, 89-94 (1997).
  14. A.E. Elsner, S. A. Burns, J. J. Weiter, and M. E. Hartnett, "Diagnostic applications of near infrared solid-state lasers in the eye," LEOS '94, IEEE Catalog number 94CH3371-2, Library of Congress number 93-61268, 1, 14-15 (1994).
  15. M E. Hartnett and A. E. Elsner, "Characteristics of exudative age-related macular degeneration determined in vivo with confocal direct and indirect infrared imaging," Ophthalmol. 103, 58-71 (1996).
  16. M. E. Hartnett, J. J. Weiter, G. Staurenghi, and A E. Elsner, "Deep retinal vascular anomalous complexes in advanced age- related macular degeneration," Ophthalmol. 103, 2042-2053 (1996).
  17. J. F. Le Gargasson, F. Rigaudiere, J. E. Guez, A. Gaudric, and Y. Grall, "Contribution of scanning laser ophthalmoscopy to the functional investigation of subjects with macular holes," Doc. Ophthalmol. 86, 227-238 (1994).
    [CrossRef] [PubMed]
  18. J.-F. Chen, A. E. Elsner, S. A. Burns, R. M. Hansen, P. L. Lou, K. K. Kwong, and A. B. Fulton, "The effect of eye shape on retinal responses," Clinical Vision Sciences 7, 521-530 (1992).
  19. W. Dreher, J. F. Bille, and R. N. Weinreb RN, "Active-optical depth resolution improvement of the laser tomographic scanner," Appl. Opt. 28, 804-808 (1988).
    [CrossRef]
  20. Remky, O. Arend, A. E. Elsner, F. Toonen, M. Reim, and S. Wolf, "Digital imaging of central serous retinopathy using infrared illumination," German J. Ophthalmology 4, 203-206 (1995).
  21. E. Beausencourt, A. E. Elsner, M. E. Hartnett, and C. L. Trempe, "Quantitative analysis of macular holes with scanning laser tomography," Ophthalmology 104, 2018-2029 (1997).
    [PubMed]
  22. C. Kunze, A. E. Elsner, E. Beausencourt, L.Moraes, M. E. Hartnett, and C. L. Trempe, "Spatial extent of pigment epithelial detachments in age-related macular degeneration," Ophthalmology 9, 1830-1840 (1999).
    [CrossRef]
  23. E. Beausencourt, A. Remky, A. E. Elsner, M. E. Hartnett, C. L. Trempe, "Infrared scanning laser tomography of macular cysts," Ophthalmology 107, 376-385 (2000).
  24. D.-U. Bartsch, M. Intaglietta, J. F. Bille, A. W. Dreher, M. Gharib, W. R. Freeman, "Confocal laser tomographic analysis of the retina in eyes with macular hole formation and other focal macular diseases," Am. J. Ophthalmol. 108, 277-87 (1989).
    [PubMed]
  25. D.-U. Bartsch and W. R. Freeman, "Axial intensity distribution analysis of the human retina with a confocal scanning laser tomograph," Exp. Eye Res. 58, 161-173 (1994).
    [CrossRef] [PubMed]
  26. C. Hudson F. G. Flanagan, G. S. Turner, D. McLeod, "Scanning laser tomography Z profile signal width as an objective index of macular retinal thickening," Br. J. Ophthalmol. 82, 121-30 (1998).
    [CrossRef] [PubMed]
  27. E. Jaakkola, I. Vesti, I. Immonen, "The use of confocal scanning laser tomography in the evaluation of retinal elevation in age-related macular degeneration," Ophthalmology 106, 274-9, (1999).
    [CrossRef] [PubMed]
  28. The link to additional figures is http://color.eri.harvard.edu/annhom.htm.
  29. Updates on infrared scanning laser topographic instrumentation are at http://www.laserdiagnostic.com.

Other

H. Leibowitz, D. E. Kruger, L. R. Maunder, R. C. Milton, M. M. Kini, H, A. Kahn, R. J. Mickerson, J. Pool, T. L. Colton, J. P. Ganley, and J. Loewenstein, "The Framingham Eye Study Monograph: an ophthalmological and epidemilogical study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973-1975," Surv. Ophthalmol. 24, (Suppl) 335-610 (1980).
[PubMed]

R. H. Webb, GW Hughes, O. Pomerantzeff, "Flying spot TV ophthalmoscope," Appl. Opt. 19 2991-2997 (1980).
[CrossRef]

R. H. Webb and G. W. Hughes, "Scanning laser ophthalmoscope," IEEE Trans. Biomed. Eng. 28, 488-492 (1981).
[CrossRef] [PubMed]

A. W. Dreher and R. N. Weinreb, "Accuracy of topographic measurements in a model eye with the laser tomographic scanner," Invest. Ophthalmol. Vis. Sci. 32, 2992-2996 (1991).
[PubMed]

R. H. Webb, G. W. Hughes, and F. C. Delori, "Confocal scanning laser ophthalmoscope," Appl. Opt. 26, 1492-1499 (1987).
[CrossRef] [PubMed]

A.W. Dreher, P.C. Tso , and R. N. Weinreb, "Reproducibility of topographic measurements of the normal and glaucomatous optic nerve head with the laser tomographic scanner," Am. J. Ophthalmol. 111, 221-229 (1991).
[PubMed]

For a review of the early infrared scanning laser techniques, see A. E. Elsner, A. H. Jalkh, A.H, and J. J. Weiter, "New devices in retinal imaging and functional evaluation," in Practical Atlas of Retinal Disease and Therapy, W. Freeman, ed. (Raven, New York, 1993) pp. 19-35. The work of several groups is found in A. E. Elsner, D-U. Bartsch, J. J. Weiter, and M. E. Hartnett, "New devices in retinal imaging and functional evaluation," in Practical Atlas of Retinal Disease and Therapy, W. Freeman, ed. (Lippincott-Raven, New York, 1998) 2nd edition, pp. 19-55.

A. E. Elsner, S.A. Burns, S.A., Kreitz, M.R., and J. J. Weiter, "New views of the retina/RPE complex: quantifying sub-retinal pathology," in Noninvasive Assessment of the Visual System, Vol. 1 of OSA Technical Digest (Optical Society of America, Washington, D.C., 1991, pp. 150-153).

A. E. Elsner, S. A. Burns, G. W. Hughes, G.W., and R. H. Webb, "Reflectometry with a Scanning Laser Ophthalmoscope," Appl. Opt. 31, 3697-3710 (1992).
[CrossRef] [PubMed]

A. E. Elsner, S. A. Burns, J. J. Weiter, and F. C. Delori, "Infrared imaging of subretinal structures in the human ocular fundus," Vision Res. 36, 191-205 (1996).
[CrossRef] [PubMed]

A. E. Elsner, A. W. Dreher, Q. Zhou, E. Beausencourt, S. A. Burns, R. H. Webb, "Multiply scattered light tomography: vertical cavity surface emitting laser array used for imaging subretinal subretinal structures," Lasers and Light in Ophthalmology 8, 193-202 (1998).

F. C. Delori, "Spectrophotometer for noninvasive measurement of intrinsic fluorescence and reflectance of the ocular fundus," Appl. Opt. 33, 7439-7452 (1994).
[CrossRef] [PubMed]

L. M. Kelley, J. P. Walker, G. L. Wing, P. A. Raskauskas, and A. E. Elsner, "Scanning laser ophthalmoscope imaging of age related macular degeneration and neoplasms," J. Ophthalmic Photography 3, 89-94 (1997).

A.E. Elsner, S. A. Burns, J. J. Weiter, and M. E. Hartnett, "Diagnostic applications of near infrared solid-state lasers in the eye," LEOS '94, IEEE Catalog number 94CH3371-2, Library of Congress number 93-61268, 1, 14-15 (1994).

M E. Hartnett and A. E. Elsner, "Characteristics of exudative age-related macular degeneration determined in vivo with confocal direct and indirect infrared imaging," Ophthalmol. 103, 58-71 (1996).

M. E. Hartnett, J. J. Weiter, G. Staurenghi, and A E. Elsner, "Deep retinal vascular anomalous complexes in advanced age- related macular degeneration," Ophthalmol. 103, 2042-2053 (1996).

J. F. Le Gargasson, F. Rigaudiere, J. E. Guez, A. Gaudric, and Y. Grall, "Contribution of scanning laser ophthalmoscopy to the functional investigation of subjects with macular holes," Doc. Ophthalmol. 86, 227-238 (1994).
[CrossRef] [PubMed]

J.-F. Chen, A. E. Elsner, S. A. Burns, R. M. Hansen, P. L. Lou, K. K. Kwong, and A. B. Fulton, "The effect of eye shape on retinal responses," Clinical Vision Sciences 7, 521-530 (1992).

W. Dreher, J. F. Bille, and R. N. Weinreb RN, "Active-optical depth resolution improvement of the laser tomographic scanner," Appl. Opt. 28, 804-808 (1988).
[CrossRef]

Remky, O. Arend, A. E. Elsner, F. Toonen, M. Reim, and S. Wolf, "Digital imaging of central serous retinopathy using infrared illumination," German J. Ophthalmology 4, 203-206 (1995).

E. Beausencourt, A. E. Elsner, M. E. Hartnett, and C. L. Trempe, "Quantitative analysis of macular holes with scanning laser tomography," Ophthalmology 104, 2018-2029 (1997).
[PubMed]

C. Kunze, A. E. Elsner, E. Beausencourt, L.Moraes, M. E. Hartnett, and C. L. Trempe, "Spatial extent of pigment epithelial detachments in age-related macular degeneration," Ophthalmology 9, 1830-1840 (1999).
[CrossRef]

E. Beausencourt, A. Remky, A. E. Elsner, M. E. Hartnett, C. L. Trempe, "Infrared scanning laser tomography of macular cysts," Ophthalmology 107, 376-385 (2000).

D.-U. Bartsch, M. Intaglietta, J. F. Bille, A. W. Dreher, M. Gharib, W. R. Freeman, "Confocal laser tomographic analysis of the retina in eyes with macular hole formation and other focal macular diseases," Am. J. Ophthalmol. 108, 277-87 (1989).
[PubMed]

D.-U. Bartsch and W. R. Freeman, "Axial intensity distribution analysis of the human retina with a confocal scanning laser tomograph," Exp. Eye Res. 58, 161-173 (1994).
[CrossRef] [PubMed]

C. Hudson F. G. Flanagan, G. S. Turner, D. McLeod, "Scanning laser tomography Z profile signal width as an objective index of macular retinal thickening," Br. J. Ophthalmol. 82, 121-30 (1998).
[CrossRef] [PubMed]

E. Jaakkola, I. Vesti, I. Immonen, "The use of confocal scanning laser tomography in the evaluation of retinal elevation in age-related macular degeneration," Ophthalmology 106, 274-9, (1999).
[CrossRef] [PubMed]

The link to additional figures is http://color.eri.harvard.edu/annhom.htm.

Updates on infrared scanning laser topographic instrumentation are at http://www.laserdiagnostic.com.

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Figures (6)

Fig. 1.
Fig. 1.

Top left- Color fundus photograph of the ocular fundus of a 77 year old female with bilateral exudative AMD. Widespread exudation covers the macula. A ring of exudates, resulting from the more central new vessel growth, is visualized as well-demarcated yellowish spots (green arrow). The choroidal new vessels (red arrow) appear near the center of the photograph. The surrounding fluid leakage is turbid, obscuring the choroid beneath it, as the choroid is readily visible in the periphery where there is no fluid. There is a crescent-shaped tear of the retinal pigment epithelium (blue arrows) on the margin of the choroidal new vessels nearest the optic nerve head. Top right- Photograph illustrating the pathological fundus changes using only short wavelength light, called “red free,” The ring of exudates appears brighter than the surrounding fundus. The choroidal new vessels and retinal pigment epithelial tear, in the center of the macula, are less well-visualized in this image. Bottom left- Early phase, photographic fluorescein angiogram of the same patient. The bright portions in the central macular region show the filling and leaking of fluorescing dye from the classic, well-defined choroidal new vessel membrane. There is initial pooling of the dye inside the ring of exudation, in some locations, which appears bright. Bottom right- Late phase fluorescein angiogram showing active leakage of fluorescein dye from the choroidal new vessels, seen as the brightest region in the macula. Adjacent is a dark region with a thin horizontal bar, corresponding to the retinal pigment epithelial tear. Surrounding this is pooling dye, with the central region darkened by the turbid fluid, which also blocks the view of the choroid.

Fig. 2.
Fig. 2.

TopSS individual images at 790 nm, showing that different sections visualize differently the ocular fundus of the patient with bilateral exudative AMD, as in Fig. 1. The pigment epithelial retinal tear, which is well beneath the retina, is readily visualized in these images. The neovascularization in the four images in this series is visualized by the dark, turbid fluid that elevates the retina, the very dark regions of hemorrhage, and the bright regions of hard exudes that have leaked from the new blood vessels. Top left- image 4 from the series of 32 images, anterior to the retina. Top right- image 9, which is slightly deeper, but still anterior to the retina. Bottom left- Image 14, which is the in the focal plane of the surface of the retina. Bottom right- Image 19, deep retina: 735µm from the retinal surface, which is elevated by the underlying exudation. The margin of the RPE tear, inferior to and left of the central portion is clearest in the image of deeper retina.

Fig. 3.
Fig. 3.

Wire frame representation of the elevation of the retina over the subretinal new vessels and fluid for the patient in Figs. 1 and 2. Far more reflective than most of tissues in the deeper layers, the vitreo-retinal interface or the nerve fiber layer is the origin of the majority of the light returning from the fundus in a confocal image.

Fig. 4.
Fig. 4.

Images of an 82 yr old male patient with exudative AMD from AMD from Ft. Myers, FL. Top left- digital color image, showing a choroidal neovascular membrane (red arrows), pigment epithelial detachment and fluid (white arrows), and leakage of serous fluid (yellow arrows). Top right- digital fluorescein angiogram (Topcon), with the choroidal neovascular membrane and leakage of serous fluid, but not visualizing the borders of the pigment epithelial detachment in this or other fluorescein images. Bottom left- early phase indocyanine green angiogram with a scanning laser opthalmoscope with 790 nm excitation (Rodenstock SLO acquired with Topcon ImageNet), showing the choroidal new vessel membrane (read arrows) but not the widespread extent of fluid leakage or clearly delineating the border of the pigment epithelial detachment in this or other image. Bottom right- late phase indocyanine green angrogram as in the adjacent panel, showing the choroidal neovascular membrane, but no leakage of the relatively large dye molecules, as expected.

Fig. 5.
Fig. 5.

Matching CT and MSLT image sections selected from the image series using the prototype instrument with the 82 yr old male patient with exudative AMD. The exudation is widespread and many components are illustrated in each single figure, although no simgle image modality in Fig. 4 shows all the parts: the classic choroidal new vessel membrane, the pigment epithelial detachment and fluid, and leakage of serous fluid. Left- For the CT image, there is good light return mainly for some of the sections in the middle of the series, when the superficial layers are in the plane of focus. The classic choroidal new vessel membrane is well-defined, and fluid is visualized in three different regions surrounding the membrane: fluid to the immediate right, the well-defined pigment epithelial detachment to the left, and additional fluid superior to the left region. As the corresponding movie shows, the deeper layers are quite dark in CT, but the superficial exudates are readily seen.. Right- Corresponding image from the 32 MSLT images, taken at the same time as the confocal series, with line-by-line alternation. This particular section shows the borders of choroidal new vessel membrane and additonal foci of exudation, such as the the pigment epithelial detachmentthat is above and to the left. More anterior sections in the movie show the top and sloping sides of the fluid exudation surrounding the choroidal new vessel membrane, as the plane of focus goes deeper and deeper. Deeper sections show the turbid fluid. [Media 1]

Fig. 6.
Fig. 6.

Confocal summary image (left) and pseudo-color height map (right), showing raised retina over fluid and the multi-component exudative lesion. At the green cross-hairs on the left and right panel, the confocal transfer function as computed and shown in the upper right panel, anterior to posterior. A corresponding movie shows the how the return of light varies from anterior to posterior sections, as well as emphasizing the different exudative features using confocal sectioning. [Media 2]

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