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Corneal Endothelial Photography
Ophthalmic Procedure Assessment
Corneal Endothelial Photography Three~year
Revision
American Academy of Ophthalmology * The purpose of the Committee on Ophthalmic Procedure Assessments is to evaluate on a scientific basis new and existing ophthalmic tests, devices, and procedures for their safety, efficacy, clinical effectiveness, and appropriate uses. Evaluations include examination of available literature, epidemiological analyses when appropriate, and compilation of opinions from recognized experts and other interested parties. After appropiate review by all contributors, including legal counsel, assessments are submitted to the Academy's Board of Trustees for consideration as official Academy policy.
Introduction Corneal endothelial photography is a procedure by which endothelial cells lining the posterior surface of the cornea in the living eye are photographed by a camera attached to a specialized specular microscope. The endothelial cell density, measured in cells per square millimeter, can be obtained from a video image or photograph. The cell density of an individual's cornea then can be compared to a previously documented cell density for that individual or to an average value of an age-matched population. Interpretation relies on estimating endothelial cell attrition and the ability of that cornea to withstand damage from trauma. Other methods of measuring endothelial cell density can provide valuable information, but corneal endothelial photography is the most accurate and is a useful tool in making a variety of clinical decisions.
Historic Background The earliest method of evaluating the corneal endothelium dates back to 1920 when Voge first reported the method of examining the endothelial mosaic by specular reflection
using the slit-lamp biomicroscope. In 1968, Maurice 2 first reported the use of a specifically designed corneal microscope to observe the endothelium at x400 magnification and coined the term specular microscope. Brown3 described a noncontact specular microscope in 1970. In 1975, Laing4 demonstrated a clinically useful microscope that could photograph the endothelium at x200. Shortly thereafter, Bourne and Kaufman5 reported results with a photographic flash attachment that allowed clearer pictures. The introduction of a clinically useful endothelial cell microscope in 1975 triggered a substantial increase in clinical and basic science research on the corneal endothelium. Prior to this time, the endothelial lining of the cornea was known to be important in maintaining corneal clarity, but its poor regenerative ability in humans was not well understood. Between 1975 and 1978, several clinical studies using the specular microscope suggested that specific intraocular events such as vitreous-endothelium touch led to corneal endothelial depletion, and the importance of minimizing endothelial trauma or touch became apparent.
The Cornea Prepared by the Committee on Ophthalmic Procedure Assessment and approved by the American Academy of Ophthalmology's Board of Trustees, September, 1996.
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The cornea is the transparent tissue forming the anterior one sixth of the wall of the eye. It provides 75%
American Academy of Ophthalmology of the focusing or refractive power of the eye, and central corneal transparency is required for clear vision. The corneal stroma (95% of the corneal thickness) is composed of tightly packed collagen fibers in an orderly arrangement. Stromal fluid swelling (edema) reduces corneal clarity by destroying this orderly arrangement. Similarly, corneal epithelial swelling reduces epithelial clarity due to intraepithelial and interepithelial haze and the loss of the smooth anterior refracting surface. A cloudy cornea misdirects or blurs light rays that pass through it. Corneal transparency requires that the cornea be maintained in a relatively deturgesced state. The corneal endothelium, a singlecell layer lining the inner surface of the cornea, acts as a barrier to the influx of aqueous humor into the stroma and pumps excess fluid out of the stroma. A healthy corneal endothelium is necessary for maintaining a transparent cornea. At birth, the normal cornea has high endothelial cell density, but these cells have minimal capacity to regenerate and replace themselves. As the eye ages, cells gradually are lost by attrition; those remaining spread out to maintain the endothelial cell monolayer. If too many cells are lost because of trauma, disease, or surgical procedures, the endothelial cell density may reach a critical lower limit at which deturgescence of the cornea can no longer be maintained. When this occurs, the cornea swells irreversibly and eventually decompensates into bullous keratopathy. The final treatment for this sometimes painful condition is surgery, usually corneal transplantation. Although corneal transplant surgery often is successful, the surgery and time of disability are costly. Sightthreatening complications can occur, and healing typically requires months before the wound is stable and vision is restored. Any direct trauma or injury to the endothelial cell layer results in a decrease in the number of cells and a decrease in endothelial reserve or the ability of the endothelium to withstand further insult. Even though the cell count may be low, the remaining endothelial cells often are capable of preventing corneal swelling until a critically low threshold is reached. A cornea of normal thickness provides little information about the endothelial cell density or corneal reserve. Determining endothelial cell density appears to be the most reliable clinical method for estimating endothelial reserve.
The Specular Microscope Several manufacturers supply specular microscopes that are designed primarily for endothelial cell counts. They range in price from $20,000 to $35,000. The image of the cells is recorded with either an attached film camera or a video camera. A reference grid is placed over the image, and all whole cells are counted in each square as well as all partial cells intersecting two of the four margins. The number obtained is multiplied by the appro-
Ophthalmic Procedure Assessment priate magnification factor to arrive at the cell density in cells per square millimeter. Most specular microscopes contact the anterior surface of the cornea to obtain the image, but some are available that do not require contact. The latter do not require a topical anesthetic, and it may be more difficult to obtain a clear image using one. Wide-field specular microscopes capture a larger area of the endothelium and allow for both qualitative and quantitative examination of a greater surface area of the cornea. Using the wide-field specular microscope, morphologic features of the corneal endothelium can be calculated accurately by computer-assisted morphometry of individual cell areas. Variation in cell area is termed polymegethism and is expressed by the coefficient of variation in cell area calculated by dividing the standard deviation of the cell area by the mean cell area. 6 ,7 Although determination of the precise coefficient of variation is a timeconsuming and tedious procedure involving computerassisted technology, Yee et al 8 have developed a rapid and convenient method of estimating the coefficient of variation by comparing photographs taken with a widefield specular microscope with endothelial tracings of predetermined cell densities and coefficients of variation. Cell shapes can be described by the number of sides of each cell. Although three-, four-, and six-sided polygons may cover a plane, only the regular hexagon covers a plane with the least amount of individual cell circumferential perimeter. 9 A regular hexagon pattern is the most stable configuration geometricallylO as well as thermodynamically,ll because it maintains the least amount of surface tension on a plane. Quantitation of variation in cell shape is called pleomorphism and may be determined by calculating the frequency of hexagonal cells. 7 Cell density determinations alone do not reflect cellular polymegethism and pleomorphism. Polymegethous endothelium has been shown to be more susceptible to surgical trauma when compared to an endothelial monolayer having uniformity in cell area. 6,12,13 Rao et al 13 demonstrated a greater incidence of postoperative corneal decompensation in eyes with pleomorphic and polymegethous endothelium shown preoperatively by specular microscopy. By contrast, Bates and Cheng 14 did not find that the development of bullous keratopathy could be predicted on the basis of preoperative or early postoperative endothelial cell morphology. Bourne et aIlS also reported that preoperative specular microscopy determinations of cell density and coefficient of variation are not predictive of postoperative endothelial cell loss after cataract surgery. Changes in endothelial morphology have been reported among patients with diabetes and long-term hard contact lens wearers. 16,17 The clinical significance of morphologic abnormalities remains uncertain.
Cell Count Accuracy The accuracy of the endothelial cell count is influenced by such factors as cell size, variation in cell area (polymegethism), total number of cells counted, clarity of the
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image, thickness of the cornea, and position of the cornea where the image is taken. If the cells are of uniform size, without areas of cornea guttata, and the image is sharp, Irvine et aI'8 found the accuracy of the cell count to be within 8%. A change in thickness of the cornea can account for a variation in cell count of only 1% to 2.5% as noted by Bourne and Enoch'9 and Laing et aI. 20 A 10% magnification of cells (creating a falsely lower cell count) can occur with cell counts in the periphery of the image, but Sugar' found this could be eliminated by ensuring that the photograph was centered in the counting grid. The original microscopes could image 5 to 75 cells within the grid, but wide-field microscopes can image as many as 1000 cells in a photograph.
Clinical Estimations of Endothelial Cell Density An estimate of the corneal endothelial cell density can be obtained by conventional slit-lamp biomicroscopic evaluation of the cornea. 22 ,23 Comparative endothelial biomicroscopy22 uses a x25 to x40 Zeiss eyepiece, with a reticule and allows the observer to view the endothelium and then compare it with an adjacent reticule, which is graduated in four steps from 500 to 4000 cells/mm 2. This technique has been reported to have a mean absolute error of 21 %, with a range from a 39% underestimation to a 105% overestimation. 24 Holladay et al 23 described quantitative endothelial biomicroscopy in which the number of endothelial cells is counted across the horizontal diameter of a 0.2mm projected spot beam of a standard biomicroscope. From the count and the known spot size, the endothelial cell density may be calculated accurately. An average error of 7% and an absolute error of 12% was calculated when compared with endothelial cell densities taken from a specular microscope. These methods of clinical estimates are less accurate than endothelial photographs, but often give sufficient information to make a clinical decision,z2,23,25 The methods for clinical estimates do not provide photographic documentation of the corneal endothelium, nor do they provide adequate information for estimation of the coefficient of variation and percentage of hexagon-shaped cells. In large studies evaluating chronic progressive endothelial cell loss related to specific intraocular lenses, methods other than the specular microscope were not accurate enough to document changes. 26 ,27
Normal Range of Cell Density It is accepted that there is a gradual decrease in endothelial
cell density with age. 28 - 30 Hoffer and Krafe' reported their analysis of routine preoperative cell counts on 2000 eyes with cataract in the 40- to 90-year age range. Their study showed that the average mean endothelial cell count is 2400 cells/mm2 for individuals 40 to 90 years of age,
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whereas the range of individuaI cell counts for these corneas is 1500 to 3500 cells/mm2. There also was an extremely small, but statistically significant, decrease in cell count with age. This large series not only defined the normal cell density, but also showed that age is not the single predictor of cell density for any given eye. Several studies32 - 34 reported a similarity between the cell density of the corneal periphery and that of the corneal center. Yee et aC showed that there is no significant vertical regional disparity or difference between paired normal corneas in cellular polymegethism or cellular pleomorphism. Sturrock et al 33 showed endothelial cell densities of both eyes of the same patient to be fairly constant. It can be concluded from these studies that the central endothelial cell count truly is representative of the entire corneal surface in normal, healthy eyes not operated on regardless of age or cell density.
Estimation of Corneal Endothelial Reserve Estimation of the endothelial reserve is made by comparing a cornea's endothelial cell count to the normal range of 1500 to 3500 cells/mm2 (age, 40-90). If the cell count is in the upper range, the cornea may be able to withstand more surgical trauma because it retains a sufficient density of endothelial cells even after greater endothelial cell loss. Conversely, if the cell count is in the lower range, the cornea may be unable to sustain as much damage, may take longer to heal, and may have a greater chance of decompensating and requiring a corneal transplant. Because of the wide range of normal cell counts, however, these comparisons are general approximations at best. Hoffer35 reported that in the extreme case of cell counts below 300 cells/mm2, the cornea decompensated and required corneal transplantation. It may be concluded that cell counts between 300 and 500 cells/mm2 are rather tenuous. Those with cell counts from 500 to 1000 cells/ mm2 should be considered at risk for decompensation on any surgical trauma. Those between 1000 and 2000 cells/ mm2 are at less risk, but still may be susceptible to corneal decompensation over time. Endothelial cell damage can occur with corneal or intraocular surgical procedures,36 blunt ocular trauma, acute and chronic uveitis, chronic elevated intraocular pressure (Boisjoly et al. When glaucoma pressures the graft. Presented at the World Congress of the Cornea IV, Orlando, Florida, 1996), intraocular lens-induced cellloss,27,28 an acute attack of narrow-angle glaucoma/7,38 and allograft rejection episodes. 39 After any of these conditions, there may be a lower than normal endothelial cell count. Although several factors may be important in assessing endothelial cell reserve, a few generalities can be made. The age of a patient is not an adequate indicator of endothelial cell density. A clear cornea of normal thickness cannot rule out a low endothelial cell count. Hoffer and Krafe' showed that 3% of normal eyes that were unoperated without cornea guttata had
American Academy of Ophthalmology a cell count lower than 1000 cells/mm 2 that was unsuspected prior to cataract surgery. In a study of patients with pseudophakic corneal edema, Waltman40 showed 17% of the contralateral eyes that were not operated on had cell counts of less than 1000 cells/mm2 despite normal slit-lamp appearance. Corneal edema develops in an eye after surgery because of one or a combination of three basic mechanisms: 1. The endothelial cell density was too low to with-
stand the trauma of the surgical procedure. 2. The cell density was normal, but the surgical procedure was excessively traumatic. 3. The patient sustained additional insult to the cornea endothelium postoperatively.
Indications for Specular Microscopy Eye Banking Specular microscopy has become widespread to evaluate donor tissue for corneal transplantation. Endothelial photography has become invaluable in assessing corneas for transplantation, making it possible to use older tissue with sufficient cell densities and eliminating donor tissue with unsuspected corneal endothelial abnormalities.25 Some eye banks routinely do specular microscopy on all tissue; other eye banks perform specular microscopy on tissue from donors 55 years of age and older. Most commonly, donor tissue with endothelial cell densities of at least 2000 cells/mm2 is made available for transplantation. In addition, the Eye Bank Association of America requires specular microscopy on all tissue from donor eyes with a history of cataract surgery before the tissue can be distributed for penetrating keratoplasty.
Ophthalmic Procedure Assessment specular microscopy is extremely helpful in assessing the risks of additional intraocular surgery. Patients with a history of ocular or orbital trauma or having unilateral cataract are more likely to have lower endothelial cell densities. Patients with a history of uveitis, angle-closure glaucoma, or intraocular inflammation may benefit from formal specular microscopy to assess the functional reserve when contemplating intraocular surgery. Corneal Disease Evaluation Specular microscopy is indicated in several specific conditions. It should be performed in patients considering secondary intraocular lens implantation. It is helpful in evaluating the patient with unilateral corneal edema, particularly in assessing the functional reserve of the contralateral eye. It is useful in evaluating the cornea prior to the removal of an intraocular lens implant for an eye in which the implant is causing chronic irritation or inflammation. In some cases, timely surgical intervention may prevent the necessity for corneal transplantation. However, surgery may precipitate corneal edema if the endothelial reserve is inadequate. If the cornea is swollen, endothelial cell counts generally are not useful, and any additional surgery will likely increase the amount of edema. Specular microscopy can be a useful tool in evaluating patients with posterior polymorphous dystrophy and the iridocorneal endothelial syndromes.41 However, the decision about whether to perform cataract surgery alone or in combination with penetrating keratoplasty in patients with endothelial or Fuchs dystrophy routinely is made according to the absence or presence of stromal edema, as determined by careful slit-lamp examination and pachymetry, not specular microscopy.
Preoperative Evaluation
Summary
Intraocular surgical procedures are now performed routinely with the aim of minimizing corneal endothelial damage. Specular microscopy is essential in evaluating the safety of new surgical procedures, intraocular lenses, and agents for intraocular use. Knowledge of the endothelial cell count before surgery is useful for better defining the surgical risks for the patient. Compared with careful slit-lamp biomicroscopy, endothelial cell photography has greater accuracy in estimating cell count, provides a permanent photographic record, and also can be used to determine the coefficient of variation in cell area and percentage of hexagonal endothelial cells, as well as to evaluate changes in these morphologic parameters over time. Prior intraocular surgery places any eye at risk for a less than normal endothelial cell density . Second or third intraocular procedures place the eye at risk for further endothelial cell loss. Because secondary intraocular lens implantation often is an elective procedure,
When properly done, corneal endothelial photography has been shown to be a relatively safe, reliable, and effective means to ascertain corneal endothelial cell density (cells/ mm2) and to provide information about endothelial cell morphometry. Currently, this procedure is not essential prior to routine cataract surgery, but may be indicated in situations in which the cornea is suspected of having endothelial abnormality and in which the accuracy of the estimated cell count from slit-lamp biomicroscopy is thought to be less than satisfactory. These situations include but are not limited to (1) eyes before secondary lens implantation; (2) eyes in which the status of the corneal endothelium is of concern because of a history of trauma, acute glaucoma, inflammation, or corneal transplantation; (3) eyes that contain intraocular lenses that are partially dislocated or are suspected of causing chronic inflammation or endothelial injury; and (4) eyes in which the fellow eye has a history of unexplained corneal edema.
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Preparation was coordinated by the Committee on Ophthalmic Procedures Assessment, with the help of the following: Proprietary interests* Revised by: COPA Cornea Panel
Elisabeth J. Cohen, MD, Chair Edward J. Holland, MD Mark J. Mannis, MD Alice Y. Matoba, MD David M. Meisler, MD Ira J. Udell, MD David C. Musch, MD
Committee on Ophthalmic Procedures Assessments:
N_______________ N_______________ N_______________ N_______________ N_______________ N_______________ N_______________ N_______________
Original draft (1991) by:
Leo J. Maguire, III, MD, Chair Elisabeth J. Cohen, MD Donald S. Fong, MD, MPH Stephen C. Gieser, MD, MPH Robert H. Kennedy, MD, PhD Donald P. Maxwell, Jr, MD Christopher J. Rapuano, MD Kenneth J. Hoffer, MD
Approved by:
Board of Directors February 23, 1991
Revision approved by:
Board of Trustees September S, 1996
Edited by:
Susan Garratt
N_______________
Managing Editor:
Rebecca Anderson
N ________
N _ _ _ _ _ _ __
N_______________
N _ _ _ _ _ _ __
N_______________
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N_______________
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*Proprietary interests stated: CATEGORY
ABBREV
SPECIFIC FINANCIAL INTERESTS
Product Investor
P Pc I
Consultant
Ie C
Financial interest in equipment, process, or product presented. Such interest in potentially competing equipment, process, or product. Financial interest in a company or companies supplying the equipment, process, or product presented. Such interest in a potentially competing company. Compensation received within the past 3 years for consulting services regarding the equipment, process, or product presented. Such compensation received for consulting services regarding potentially competing equipment, process, or product.
Cc
None
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C1 C2 C3 C4 CS C6 C7 CS N
or or or or or or or or
Cc1 Cc2 Cc3 Cc4 CcS Cc6 Cc7 CcS
EXAMPLES OF COMPENSA nON RECEIVED INCLUDE: 1. Retainer 2. Contract payments for research performed 3. Ad hoc consulting fees 4. Substantial nonmonetary perquisites S. Contribution to research or research funds 6. Contribution to travel funds 7. Reimbursement of travel expenses for presentation at meetings or courses S. Reimbursement of travel expenses for periods of direct consultation No financial interest. May be stated when such interests might falsely be suspected.
American Academy of Ophthalmology . Ophthalmic Procedure Assessment
References 1. Vogt A. Die Sichtbarkeit des lebenden Hornhautendothels: ein Beitrag zur Methodik der Spaltlampenrnikroskopie. Albrecht von Graefes Klin Exp Ophthalmol 1920; 101:123-44. 2. Maurice DM. Cellular membrane activity in the corneal endothelium of the intact eye. Experientia 1968;24:1094-5. 3. Brown N. Macrophotography of the anterior segment of the eye. Br J Ophthalmol 1975; 54:697 -701. 4. Laing RA. In vivo photomicrography of the corneal endothelium. Arch OphthalmolI975;93:l43-5. 5. Bourne WM, Kaufman HE. Specular microscopy of the human corneal endothelium in vivo. Am J Ophthalmol 1976;81:319-23. 6. Shaw EL, Rao GN, Arthur EJ, Aquavella JV. The functional reserve of corneal endothelium. Trans Am Acad OphthalmolOtolaryngol 1978;85:640-9. 7. Yee RW, Matsuda M, Schultz RO, Edelhauser HF. Changes in the normal corneal endothelial cellular pattern as a function of age. Curr Eye Res 1985;4:671-8. 8. Yee RW, Matsuda M, Edelhauser HF. Wide-field endothelial counting panels (Letter). Am J Ophthalmol 1985;99:596-7. 9. Thompson DW. The forms of tissues on cell-aggregates. In: Bonner JT, ed. On Growth and Form. Cambridge: University Press, 1982; 88 -119. 10. Rao GN, Lohman LE, Aquavella JV. Cell-size-shape relationships in corneal endothelium. Invest Ophthalmol Vis Sci 1982;22:271-4. 11. Tanimura K. A quantitative analysis of corneal endothelial cells. Folia Ophthalmol Jpn 1981;32:1835-9. 12. Bourne WM, Brubaker RF, O'Fallon M. Use of air to decrease endothelial cell loss during intraocular lens implantation. Arch OphthalmoI1979;97:1473-5. 13. Rao GN, Aquavella JV, Goldberg SH, Berk SL. Pseudophakic bullous keratopathy: relationship to preoperative corneal endothelial status. Ophthalmology 1984;91:1135-40. 14. Bates AK, Cheng H. Bullous keratopathy: a study of endothelial cell morphology in patients undergoing cataract surgery. Br J OphthalmoI1988;72:409-12. 15. Bourne WM, Nelson LR, Hodge DO. Continued endothelial cell loss ten years after lens implantation. Ophthalmology 1994; 101: 1014-23. 16. Keoleian GM, Pach JM, Hodge DO, et al. Structural and functional studies of the corneal endothelium in diabetes mellitus. Am J Ophthalmol 1992; 113:64-70. 17. Sibug ME, Datiles MB, Kashma K, et al. Specular microscopy studies on the corneal endothelium after cessation of contact lens wear. Cornea 1991; 10:395-401. 18. Irvine AR, Kratz RP, O'Donnell JJ. Endothelial damage with phacoemulsification and intraocular lens implantation. Arch Ophthalmol 1978;96:1023-6. 19. Bourne WM, Enoch JM. Some optical principles of the clinical specular microscope. Invest Ophthalmol Vis Sci 1976; 15:29-32. 20. Laing RA, Sandstrom MN, Berrospi AR, Leibowitz HM. Morphological changes in corneal endothelial cells after penetrating keratoplasty. Am J Ophthalmol 1976;82:45964. 21. Sugar A. Clinical specular microscopy. Surv Ophthalmol 1979; 24:21- 32. 22. McIntyre DJ. Comparative endothelial biomicroscopy. Am Intra-Ocular Implant Soc J 1979;5:346-8.
23. Holladay JT, Bishop JE, Prager Te. Quantitative endothelial biomicroscopy. Ophthalmic Surg 1983; 14:33-40. 24. Waring GO III, Bourne WM, Edelhauser HF, et al. The corneal endothelium. Normal and pathologic structure and function. Ophthalmology 1982;89:531-90. 25. Hirst LW. Assessment of the corneal endothelium prior to cataract and corneal graft surgery. Aust N Z J Ophthalmol 1988; 16:273-4. 26. Kraff MC, Sanders DR, Lieberman HL. Monitoring for continuing endothelial cell loss with cataract extraction and intraocular lens implantation. Ophthalmology 1982; 89:304. 27. Stark WJ, Maumenee AE, Dangel ME, et al. Intraocular lenses. Experience at the Wilmer Institute. Ophthalmology 1982;89:104-8. 28. Laing RA, Sandstrom MN, Berrospi AR, Leibowitz HM. Changes in the corneal endothelium as a function of age. Exp Eye Res 1976;22:587-94. 29. Laule A, Cable MK, Hoffman CE, Hanna e. Endothelial cell population changes of human cornea during life. Arch OphthalmoI1978;96:2031-5. 30. Cardoza OL. Cellular density of normal corneal endothelium. Doc Ophthalmol 1979;46:201-6. 31. Hoffer KJ, Kraff Me. Normal endothelial cell count range. Ophthalmology 1980;87:861-5. 32. Hoffer KJ. Vertical endothelial cell disparity. Am J OphthalmoI1979;87:344-9. 33. Sturrock GD, Sherrard ES, Rice NSe. Specular microscopy of the corneal endothelium. Br J OphthalmoI1978;62:80914. 34. Blackwell WL, Gravenstein N, Kaufman HE. Comparison of central corneal endothelial cell numbers with peripheral areas. Am J Ophthalmol 1977;84:473-6. 35. Hoffer KJ. Corneal decompensation after corneal endothelium cell count. Am J Ophthalmol 1979;87:252-3. 36. Bourne WM, McCarey BE, Kaufman HE. Clinical specular microscopy. Trans Am Acad Ophthalmol Otolaryngol 1976;81:743-53. 37. Olsen T. The endothelial cell damage in acute glaucoma. On the corneal thickness response to intraocular pressure. Acta Ophthalmol 1980; 58:257 -66. 38. Bigar F, Wilmer R. Corneal endothelial changes in primary acute angle-closure glaucoma. Ophthalmology 1982;89:5969. 39. Musch DC, Schwartz AE, Fitzgerald-Shelton K, et al. The effect of allograft rejection after penetrating keratoplasty on central endothelial cell density. Am J Ophthalmol 1991; 111 :739-42. 40. Waltman SR. Penetrating keratoplasty for pseudophakic bullous keratoplasty. Arch Ophthalmol 1981;99:415-6. 41. Laganowski HC, Muir MGK, Hitching RA. Glaucoma and the iridocorneal endothelial syndrome. Arch Ophthalmol 1992; 110:346-50.
Related Academy Materials Basic Clinical and Science Course: External Disease and Cornea (1996-1997, Section 8). Focal Points: Clinical Modules for Ophthalmologists: Hirst LW: Clinical Evaluation of the Corneal Endothelium (1986, Module 8).
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Corneal Endothelial Photography Three~year
Revision
American Academy of Ophthalmology * The purpose of the Committee on Ophthalmic Procedure Assessments is to evaluate on a scientific basis new and existing ophthalmic tests, devices, and procedures for their safety, efficacy, clinical effectiveness, and appropriate uses. Evaluations include examination of available literature, epidemiological analyses when appropriate, and compilation of opinions from recognized experts and other interested parties. After appropiate review by all contributors, including legal counsel, assessments are submitted to the Academy's Board of Trustees for consideration as official Academy policy.
Introduction Corneal endothelial photography is a procedure by which endothelial cells lining the posterior surface of the cornea in the living eye are photographed by a camera attached to a specialized specular microscope. The endothelial cell density, measured in cells per square millimeter, can be obtained from a video image or photograph. The cell density of an individual's cornea then can be compared to a previously documented cell density for that individual or to an average value of an age-matched population. Interpretation relies on estimating endothelial cell attrition and the ability of that cornea to withstand damage from trauma. Other methods of measuring endothelial cell density can provide valuable information, but corneal endothelial photography is the most accurate and is a useful tool in making a variety of clinical decisions.
Historic Background The earliest method of evaluating the corneal endothelium dates back to 1920 when Voge first reported the method of examining the endothelial mosaic by specular reflection
using the slit-lamp biomicroscope. In 1968, Maurice 2 first reported the use of a specifically designed corneal microscope to observe the endothelium at x400 magnification and coined the term specular microscope. Brown3 described a noncontact specular microscope in 1970. In 1975, Laing4 demonstrated a clinically useful microscope that could photograph the endothelium at x200. Shortly thereafter, Bourne and Kaufman5 reported results with a photographic flash attachment that allowed clearer pictures. The introduction of a clinically useful endothelial cell microscope in 1975 triggered a substantial increase in clinical and basic science research on the corneal endothelium. Prior to this time, the endothelial lining of the cornea was known to be important in maintaining corneal clarity, but its poor regenerative ability in humans was not well understood. Between 1975 and 1978, several clinical studies using the specular microscope suggested that specific intraocular events such as vitreous-endothelium touch led to corneal endothelial depletion, and the importance of minimizing endothelial trauma or touch became apparent.
The Cornea Prepared by the Committee on Ophthalmic Procedure Assessment and approved by the American Academy of Ophthalmology's Board of Trustees, September, 1996.
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The cornea is the transparent tissue forming the anterior one sixth of the wall of the eye. It provides 75%
American Academy of Ophthalmology of the focusing or refractive power of the eye, and central corneal transparency is required for clear vision. The corneal stroma (95% of the corneal thickness) is composed of tightly packed collagen fibers in an orderly arrangement. Stromal fluid swelling (edema) reduces corneal clarity by destroying this orderly arrangement. Similarly, corneal epithelial swelling reduces epithelial clarity due to intraepithelial and interepithelial haze and the loss of the smooth anterior refracting surface. A cloudy cornea misdirects or blurs light rays that pass through it. Corneal transparency requires that the cornea be maintained in a relatively deturgesced state. The corneal endothelium, a singlecell layer lining the inner surface of the cornea, acts as a barrier to the influx of aqueous humor into the stroma and pumps excess fluid out of the stroma. A healthy corneal endothelium is necessary for maintaining a transparent cornea. At birth, the normal cornea has high endothelial cell density, but these cells have minimal capacity to regenerate and replace themselves. As the eye ages, cells gradually are lost by attrition; those remaining spread out to maintain the endothelial cell monolayer. If too many cells are lost because of trauma, disease, or surgical procedures, the endothelial cell density may reach a critical lower limit at which deturgescence of the cornea can no longer be maintained. When this occurs, the cornea swells irreversibly and eventually decompensates into bullous keratopathy. The final treatment for this sometimes painful condition is surgery, usually corneal transplantation. Although corneal transplant surgery often is successful, the surgery and time of disability are costly. Sightthreatening complications can occur, and healing typically requires months before the wound is stable and vision is restored. Any direct trauma or injury to the endothelial cell layer results in a decrease in the number of cells and a decrease in endothelial reserve or the ability of the endothelium to withstand further insult. Even though the cell count may be low, the remaining endothelial cells often are capable of preventing corneal swelling until a critically low threshold is reached. A cornea of normal thickness provides little information about the endothelial cell density or corneal reserve. Determining endothelial cell density appears to be the most reliable clinical method for estimating endothelial reserve.
The Specular Microscope Several manufacturers supply specular microscopes that are designed primarily for endothelial cell counts. They range in price from $20,000 to $35,000. The image of the cells is recorded with either an attached film camera or a video camera. A reference grid is placed over the image, and all whole cells are counted in each square as well as all partial cells intersecting two of the four margins. The number obtained is multiplied by the appro-
Ophthalmic Procedure Assessment priate magnification factor to arrive at the cell density in cells per square millimeter. Most specular microscopes contact the anterior surface of the cornea to obtain the image, but some are available that do not require contact. The latter do not require a topical anesthetic, and it may be more difficult to obtain a clear image using one. Wide-field specular microscopes capture a larger area of the endothelium and allow for both qualitative and quantitative examination of a greater surface area of the cornea. Using the wide-field specular microscope, morphologic features of the corneal endothelium can be calculated accurately by computer-assisted morphometry of individual cell areas. Variation in cell area is termed polymegethism and is expressed by the coefficient of variation in cell area calculated by dividing the standard deviation of the cell area by the mean cell area. 6 ,7 Although determination of the precise coefficient of variation is a timeconsuming and tedious procedure involving computerassisted technology, Yee et al 8 have developed a rapid and convenient method of estimating the coefficient of variation by comparing photographs taken with a widefield specular microscope with endothelial tracings of predetermined cell densities and coefficients of variation. Cell shapes can be described by the number of sides of each cell. Although three-, four-, and six-sided polygons may cover a plane, only the regular hexagon covers a plane with the least amount of individual cell circumferential perimeter. 9 A regular hexagon pattern is the most stable configuration geometricallylO as well as thermodynamically,ll because it maintains the least amount of surface tension on a plane. Quantitation of variation in cell shape is called pleomorphism and may be determined by calculating the frequency of hexagonal cells. 7 Cell density determinations alone do not reflect cellular polymegethism and pleomorphism. Polymegethous endothelium has been shown to be more susceptible to surgical trauma when compared to an endothelial monolayer having uniformity in cell area. 6,12,13 Rao et al 13 demonstrated a greater incidence of postoperative corneal decompensation in eyes with pleomorphic and polymegethous endothelium shown preoperatively by specular microscopy. By contrast, Bates and Cheng 14 did not find that the development of bullous keratopathy could be predicted on the basis of preoperative or early postoperative endothelial cell morphology. Bourne et aIlS also reported that preoperative specular microscopy determinations of cell density and coefficient of variation are not predictive of postoperative endothelial cell loss after cataract surgery. Changes in endothelial morphology have been reported among patients with diabetes and long-term hard contact lens wearers. 16,17 The clinical significance of morphologic abnormalities remains uncertain.
Cell Count Accuracy The accuracy of the endothelial cell count is influenced by such factors as cell size, variation in cell area (polymegethism), total number of cells counted, clarity of the
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Volume 104, Number 8, August 1997
image, thickness of the cornea, and position of the cornea where the image is taken. If the cells are of uniform size, without areas of cornea guttata, and the image is sharp, Irvine et aI'8 found the accuracy of the cell count to be within 8%. A change in thickness of the cornea can account for a variation in cell count of only 1% to 2.5% as noted by Bourne and Enoch'9 and Laing et aI. 20 A 10% magnification of cells (creating a falsely lower cell count) can occur with cell counts in the periphery of the image, but Sugar' found this could be eliminated by ensuring that the photograph was centered in the counting grid. The original microscopes could image 5 to 75 cells within the grid, but wide-field microscopes can image as many as 1000 cells in a photograph.
Clinical Estimations of Endothelial Cell Density An estimate of the corneal endothelial cell density can be obtained by conventional slit-lamp biomicroscopic evaluation of the cornea. 22 ,23 Comparative endothelial biomicroscopy22 uses a x25 to x40 Zeiss eyepiece, with a reticule and allows the observer to view the endothelium and then compare it with an adjacent reticule, which is graduated in four steps from 500 to 4000 cells/mm 2. This technique has been reported to have a mean absolute error of 21 %, with a range from a 39% underestimation to a 105% overestimation. 24 Holladay et al 23 described quantitative endothelial biomicroscopy in which the number of endothelial cells is counted across the horizontal diameter of a 0.2mm projected spot beam of a standard biomicroscope. From the count and the known spot size, the endothelial cell density may be calculated accurately. An average error of 7% and an absolute error of 12% was calculated when compared with endothelial cell densities taken from a specular microscope. These methods of clinical estimates are less accurate than endothelial photographs, but often give sufficient information to make a clinical decision,z2,23,25 The methods for clinical estimates do not provide photographic documentation of the corneal endothelium, nor do they provide adequate information for estimation of the coefficient of variation and percentage of hexagon-shaped cells. In large studies evaluating chronic progressive endothelial cell loss related to specific intraocular lenses, methods other than the specular microscope were not accurate enough to document changes. 26 ,27
Normal Range of Cell Density It is accepted that there is a gradual decrease in endothelial
cell density with age. 28 - 30 Hoffer and Krafe' reported their analysis of routine preoperative cell counts on 2000 eyes with cataract in the 40- to 90-year age range. Their study showed that the average mean endothelial cell count is 2400 cells/mm2 for individuals 40 to 90 years of age,
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whereas the range of individuaI cell counts for these corneas is 1500 to 3500 cells/mm2. There also was an extremely small, but statistically significant, decrease in cell count with age. This large series not only defined the normal cell density, but also showed that age is not the single predictor of cell density for any given eye. Several studies32 - 34 reported a similarity between the cell density of the corneal periphery and that of the corneal center. Yee et aC showed that there is no significant vertical regional disparity or difference between paired normal corneas in cellular polymegethism or cellular pleomorphism. Sturrock et al 33 showed endothelial cell densities of both eyes of the same patient to be fairly constant. It can be concluded from these studies that the central endothelial cell count truly is representative of the entire corneal surface in normal, healthy eyes not operated on regardless of age or cell density.
Estimation of Corneal Endothelial Reserve Estimation of the endothelial reserve is made by comparing a cornea's endothelial cell count to the normal range of 1500 to 3500 cells/mm2 (age, 40-90). If the cell count is in the upper range, the cornea may be able to withstand more surgical trauma because it retains a sufficient density of endothelial cells even after greater endothelial cell loss. Conversely, if the cell count is in the lower range, the cornea may be unable to sustain as much damage, may take longer to heal, and may have a greater chance of decompensating and requiring a corneal transplant. Because of the wide range of normal cell counts, however, these comparisons are general approximations at best. Hoffer35 reported that in the extreme case of cell counts below 300 cells/mm2, the cornea decompensated and required corneal transplantation. It may be concluded that cell counts between 300 and 500 cells/mm2 are rather tenuous. Those with cell counts from 500 to 1000 cells/ mm2 should be considered at risk for decompensation on any surgical trauma. Those between 1000 and 2000 cells/ mm2 are at less risk, but still may be susceptible to corneal decompensation over time. Endothelial cell damage can occur with corneal or intraocular surgical procedures,36 blunt ocular trauma, acute and chronic uveitis, chronic elevated intraocular pressure (Boisjoly et al. When glaucoma pressures the graft. Presented at the World Congress of the Cornea IV, Orlando, Florida, 1996), intraocular lens-induced cellloss,27,28 an acute attack of narrow-angle glaucoma/7,38 and allograft rejection episodes. 39 After any of these conditions, there may be a lower than normal endothelial cell count. Although several factors may be important in assessing endothelial cell reserve, a few generalities can be made. The age of a patient is not an adequate indicator of endothelial cell density. A clear cornea of normal thickness cannot rule out a low endothelial cell count. Hoffer and Krafe' showed that 3% of normal eyes that were unoperated without cornea guttata had
American Academy of Ophthalmology a cell count lower than 1000 cells/mm 2 that was unsuspected prior to cataract surgery. In a study of patients with pseudophakic corneal edema, Waltman40 showed 17% of the contralateral eyes that were not operated on had cell counts of less than 1000 cells/mm2 despite normal slit-lamp appearance. Corneal edema develops in an eye after surgery because of one or a combination of three basic mechanisms: 1. The endothelial cell density was too low to with-
stand the trauma of the surgical procedure. 2. The cell density was normal, but the surgical procedure was excessively traumatic. 3. The patient sustained additional insult to the cornea endothelium postoperatively.
Indications for Specular Microscopy Eye Banking Specular microscopy has become widespread to evaluate donor tissue for corneal transplantation. Endothelial photography has become invaluable in assessing corneas for transplantation, making it possible to use older tissue with sufficient cell densities and eliminating donor tissue with unsuspected corneal endothelial abnormalities.25 Some eye banks routinely do specular microscopy on all tissue; other eye banks perform specular microscopy on tissue from donors 55 years of age and older. Most commonly, donor tissue with endothelial cell densities of at least 2000 cells/mm2 is made available for transplantation. In addition, the Eye Bank Association of America requires specular microscopy on all tissue from donor eyes with a history of cataract surgery before the tissue can be distributed for penetrating keratoplasty.
Ophthalmic Procedure Assessment specular microscopy is extremely helpful in assessing the risks of additional intraocular surgery. Patients with a history of ocular or orbital trauma or having unilateral cataract are more likely to have lower endothelial cell densities. Patients with a history of uveitis, angle-closure glaucoma, or intraocular inflammation may benefit from formal specular microscopy to assess the functional reserve when contemplating intraocular surgery. Corneal Disease Evaluation Specular microscopy is indicated in several specific conditions. It should be performed in patients considering secondary intraocular lens implantation. It is helpful in evaluating the patient with unilateral corneal edema, particularly in assessing the functional reserve of the contralateral eye. It is useful in evaluating the cornea prior to the removal of an intraocular lens implant for an eye in which the implant is causing chronic irritation or inflammation. In some cases, timely surgical intervention may prevent the necessity for corneal transplantation. However, surgery may precipitate corneal edema if the endothelial reserve is inadequate. If the cornea is swollen, endothelial cell counts generally are not useful, and any additional surgery will likely increase the amount of edema. Specular microscopy can be a useful tool in evaluating patients with posterior polymorphous dystrophy and the iridocorneal endothelial syndromes.41 However, the decision about whether to perform cataract surgery alone or in combination with penetrating keratoplasty in patients with endothelial or Fuchs dystrophy routinely is made according to the absence or presence of stromal edema, as determined by careful slit-lamp examination and pachymetry, not specular microscopy.
Preoperative Evaluation
Summary
Intraocular surgical procedures are now performed routinely with the aim of minimizing corneal endothelial damage. Specular microscopy is essential in evaluating the safety of new surgical procedures, intraocular lenses, and agents for intraocular use. Knowledge of the endothelial cell count before surgery is useful for better defining the surgical risks for the patient. Compared with careful slit-lamp biomicroscopy, endothelial cell photography has greater accuracy in estimating cell count, provides a permanent photographic record, and also can be used to determine the coefficient of variation in cell area and percentage of hexagonal endothelial cells, as well as to evaluate changes in these morphologic parameters over time. Prior intraocular surgery places any eye at risk for a less than normal endothelial cell density . Second or third intraocular procedures place the eye at risk for further endothelial cell loss. Because secondary intraocular lens implantation often is an elective procedure,
When properly done, corneal endothelial photography has been shown to be a relatively safe, reliable, and effective means to ascertain corneal endothelial cell density (cells/ mm2) and to provide information about endothelial cell morphometry. Currently, this procedure is not essential prior to routine cataract surgery, but may be indicated in situations in which the cornea is suspected of having endothelial abnormality and in which the accuracy of the estimated cell count from slit-lamp biomicroscopy is thought to be less than satisfactory. These situations include but are not limited to (1) eyes before secondary lens implantation; (2) eyes in which the status of the corneal endothelium is of concern because of a history of trauma, acute glaucoma, inflammation, or corneal transplantation; (3) eyes that contain intraocular lenses that are partially dislocated or are suspected of causing chronic inflammation or endothelial injury; and (4) eyes in which the fellow eye has a history of unexplained corneal edema.
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Ophthalmology
Volume 104, Number 8, August 1997
Preparation was coordinated by the Committee on Ophthalmic Procedures Assessment, with the help of the following: Proprietary interests* Revised by: COPA Cornea Panel
Elisabeth J. Cohen, MD, Chair Edward J. Holland, MD Mark J. Mannis, MD Alice Y. Matoba, MD David M. Meisler, MD Ira J. Udell, MD David C. Musch, MD
Committee on Ophthalmic Procedures Assessments:
N_______________ N_______________ N_______________ N_______________ N_______________ N_______________ N_______________ N_______________
Original draft (1991) by:
Leo J. Maguire, III, MD, Chair Elisabeth J. Cohen, MD Donald S. Fong, MD, MPH Stephen C. Gieser, MD, MPH Robert H. Kennedy, MD, PhD Donald P. Maxwell, Jr, MD Christopher J. Rapuano, MD Kenneth J. Hoffer, MD
Approved by:
Board of Directors February 23, 1991
Revision approved by:
Board of Trustees September S, 1996
Edited by:
Susan Garratt
N_______________
Managing Editor:
Rebecca Anderson
N ________
N _ _ _ _ _ _ __
N_______________
N _ _ _ _ _ _ __
N_______________
N _ _ _ _ _ _ __
N_______________
N _ _ _ _ _ __
*Proprietary interests stated: CATEGORY
ABBREV
SPECIFIC FINANCIAL INTERESTS
Product Investor
P Pc I
Consultant
Ie C
Financial interest in equipment, process, or product presented. Such interest in potentially competing equipment, process, or product. Financial interest in a company or companies supplying the equipment, process, or product presented. Such interest in a potentially competing company. Compensation received within the past 3 years for consulting services regarding the equipment, process, or product presented. Such compensation received for consulting services regarding potentially competing equipment, process, or product.
Cc
None
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C1 C2 C3 C4 CS C6 C7 CS N
or or or or or or or or
Cc1 Cc2 Cc3 Cc4 CcS Cc6 Cc7 CcS
EXAMPLES OF COMPENSA nON RECEIVED INCLUDE: 1. Retainer 2. Contract payments for research performed 3. Ad hoc consulting fees 4. Substantial nonmonetary perquisites S. Contribution to research or research funds 6. Contribution to travel funds 7. Reimbursement of travel expenses for presentation at meetings or courses S. Reimbursement of travel expenses for periods of direct consultation No financial interest. May be stated when such interests might falsely be suspected.
American Academy of Ophthalmology . Ophthalmic Procedure Assessment
References 1. Vogt A. Die Sichtbarkeit des lebenden Hornhautendothels: ein Beitrag zur Methodik der Spaltlampenrnikroskopie. Albrecht von Graefes Klin Exp Ophthalmol 1920; 101:123-44. 2. Maurice DM. Cellular membrane activity in the corneal endothelium of the intact eye. Experientia 1968;24:1094-5. 3. Brown N. Macrophotography of the anterior segment of the eye. Br J Ophthalmol 1975; 54:697 -701. 4. Laing RA. In vivo photomicrography of the corneal endothelium. Arch OphthalmolI975;93:l43-5. 5. Bourne WM, Kaufman HE. Specular microscopy of the human corneal endothelium in vivo. Am J Ophthalmol 1976;81:319-23. 6. Shaw EL, Rao GN, Arthur EJ, Aquavella JV. The functional reserve of corneal endothelium. Trans Am Acad OphthalmolOtolaryngol 1978;85:640-9. 7. Yee RW, Matsuda M, Schultz RO, Edelhauser HF. Changes in the normal corneal endothelial cellular pattern as a function of age. Curr Eye Res 1985;4:671-8. 8. Yee RW, Matsuda M, Edelhauser HF. Wide-field endothelial counting panels (Letter). Am J Ophthalmol 1985;99:596-7. 9. Thompson DW. The forms of tissues on cell-aggregates. In: Bonner JT, ed. On Growth and Form. Cambridge: University Press, 1982; 88 -119. 10. Rao GN, Lohman LE, Aquavella JV. Cell-size-shape relationships in corneal endothelium. Invest Ophthalmol Vis Sci 1982;22:271-4. 11. Tanimura K. A quantitative analysis of corneal endothelial cells. Folia Ophthalmol Jpn 1981;32:1835-9. 12. Bourne WM, Brubaker RF, O'Fallon M. Use of air to decrease endothelial cell loss during intraocular lens implantation. Arch OphthalmoI1979;97:1473-5. 13. Rao GN, Aquavella JV, Goldberg SH, Berk SL. Pseudophakic bullous keratopathy: relationship to preoperative corneal endothelial status. Ophthalmology 1984;91:1135-40. 14. Bates AK, Cheng H. Bullous keratopathy: a study of endothelial cell morphology in patients undergoing cataract surgery. Br J OphthalmoI1988;72:409-12. 15. Bourne WM, Nelson LR, Hodge DO. Continued endothelial cell loss ten years after lens implantation. Ophthalmology 1994; 101: 1014-23. 16. Keoleian GM, Pach JM, Hodge DO, et al. Structural and functional studies of the corneal endothelium in diabetes mellitus. Am J Ophthalmol 1992; 113:64-70. 17. Sibug ME, Datiles MB, Kashma K, et al. Specular microscopy studies on the corneal endothelium after cessation of contact lens wear. Cornea 1991; 10:395-401. 18. Irvine AR, Kratz RP, O'Donnell JJ. Endothelial damage with phacoemulsification and intraocular lens implantation. Arch Ophthalmol 1978;96:1023-6. 19. Bourne WM, Enoch JM. Some optical principles of the clinical specular microscope. Invest Ophthalmol Vis Sci 1976; 15:29-32. 20. Laing RA, Sandstrom MN, Berrospi AR, Leibowitz HM. Morphological changes in corneal endothelial cells after penetrating keratoplasty. Am J Ophthalmol 1976;82:45964. 21. Sugar A. Clinical specular microscopy. Surv Ophthalmol 1979; 24:21- 32. 22. McIntyre DJ. Comparative endothelial biomicroscopy. Am Intra-Ocular Implant Soc J 1979;5:346-8.
23. Holladay JT, Bishop JE, Prager Te. Quantitative endothelial biomicroscopy. Ophthalmic Surg 1983; 14:33-40. 24. Waring GO III, Bourne WM, Edelhauser HF, et al. The corneal endothelium. Normal and pathologic structure and function. Ophthalmology 1982;89:531-90. 25. Hirst LW. Assessment of the corneal endothelium prior to cataract and corneal graft surgery. Aust N Z J Ophthalmol 1988; 16:273-4. 26. Kraff MC, Sanders DR, Lieberman HL. Monitoring for continuing endothelial cell loss with cataract extraction and intraocular lens implantation. Ophthalmology 1982; 89:304. 27. Stark WJ, Maumenee AE, Dangel ME, et al. Intraocular lenses. Experience at the Wilmer Institute. Ophthalmology 1982;89:104-8. 28. Laing RA, Sandstrom MN, Berrospi AR, Leibowitz HM. Changes in the corneal endothelium as a function of age. Exp Eye Res 1976;22:587-94. 29. Laule A, Cable MK, Hoffman CE, Hanna e. Endothelial cell population changes of human cornea during life. Arch OphthalmoI1978;96:2031-5. 30. Cardoza OL. Cellular density of normal corneal endothelium. Doc Ophthalmol 1979;46:201-6. 31. Hoffer KJ, Kraff Me. Normal endothelial cell count range. Ophthalmology 1980;87:861-5. 32. Hoffer KJ. Vertical endothelial cell disparity. Am J OphthalmoI1979;87:344-9. 33. Sturrock GD, Sherrard ES, Rice NSe. Specular microscopy of the corneal endothelium. Br J OphthalmoI1978;62:80914. 34. Blackwell WL, Gravenstein N, Kaufman HE. Comparison of central corneal endothelial cell numbers with peripheral areas. Am J Ophthalmol 1977;84:473-6. 35. Hoffer KJ. Corneal decompensation after corneal endothelium cell count. Am J Ophthalmol 1979;87:252-3. 36. Bourne WM, McCarey BE, Kaufman HE. Clinical specular microscopy. Trans Am Acad Ophthalmol Otolaryngol 1976;81:743-53. 37. Olsen T. The endothelial cell damage in acute glaucoma. On the corneal thickness response to intraocular pressure. Acta Ophthalmol 1980; 58:257 -66. 38. Bigar F, Wilmer R. Corneal endothelial changes in primary acute angle-closure glaucoma. Ophthalmology 1982;89:5969. 39. Musch DC, Schwartz AE, Fitzgerald-Shelton K, et al. The effect of allograft rejection after penetrating keratoplasty on central endothelial cell density. Am J Ophthalmol 1991; 111 :739-42. 40. Waltman SR. Penetrating keratoplasty for pseudophakic bullous keratoplasty. Arch Ophthalmol 1981;99:415-6. 41. Laganowski HC, Muir MGK, Hitching RA. Glaucoma and the iridocorneal endothelial syndrome. Arch Ophthalmol 1992; 110:346-50.
Related Academy Materials Basic Clinical and Science Course: External Disease and Cornea (1996-1997, Section 8). Focal Points: Clinical Modules for Ophthalmologists: Hirst LW: Clinical Evaluation of the Corneal Endothelium (1986, Module 8).
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