Effects of Phocoemulsificotion and Extracapsular Lens Removal on Corneal Thickness and Endothelial Cell Density in the Dog

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Effects of Phocoemulsificotion and Extracapsular Lens Removal on Corneal Thickness and Endothelial Cell Density in the Dog Robert M. Gwin, J. Kay Warren, Donald A. Samuelson, and Glenwood G.

1 Effects of Phocoemulsificotion and Extracapsular Lens Removal on Corneal Thickness and Endothelial Cell Density in the Dog Robert M. Gwin, J. Kay Warren, Donald A. Samuelson, and Glenwood G. Gum Twenty-one dogs were used to study the effects of phacoemulsification and extracapsular lens removal on corneal endothelium and corneal thickness. Specular microscopy revealed preoperative cell morphology and cell densities similar to man. After surgery endothelial cell counts significantly decreased 22% (central) and 13% (periphery) with phacoemulsification and 34% (central) and 31% (periphery) with extracapsular lens removal. Corneal thickness increased with both procedures. Endothelial cell pathology included cellular enlargement, increased pleomorphism, and focal cellular degeneration. Phacoemulsification time did not correlate with the degree of cell loss. Dog corneal endothelium responds to surgical trauma in a manner similar to man and maintains a functional monolayer via cellular enlargement and migration. The dog, therefore, represents a good animal model for the study of corneal endothelial disease in man. Invest Ophthalmol Vis Sci 24: , 1983 With the advent of ultrasonic instrumentation for the removal of cataractous lenses, cataract surgery in man has been significantly modified. 1 While many advantages are derived from phacoemulsification, potential degeneration or destruction of the corneal endothelium is a significant problem. Corneal endothelial cell lesions may be associated with heat produced at the tip of the ultrasonic probe, irrigation of the anterior chamber with a variety of irrigation solutions, vibration of the ultrasonic probe, mechanical damage from lens cortical and nuclear material, and instrumentation. 2 " 4 Resulting corneal edema may be severe. Endothelial cell loss following lens removal is variable in man. Phacoemulsification in man results in endothelial cell loss commonly ranging from 18 to 34%, 5 ~ 6 while intracapsular lens extraction cell loss may range from 12 to 15%. 6 " 7 Additional procedures such as intraocular lens implantation result in additional endothelial cell losses. 5 " 7 Human endothelial cell densities decrease with age as well as following surgical trauma. 8 " 9 This is asso- From the Division of Comparative Ophthalmology, Department of Special Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida. Supported in part by NIH Training Grant T32EY070. Submitted for publication June 22, Reprint requests: Robert M. Gwin, D.V.M., Dean A. McGee Eye Institute, 8 Stanton L. Young Boulevard, Oklahoma City, OK ciated with a tendency for human corneal endothelial cells to enlarge and migrate to maintain a functional monolayer rather than maintaining a monolayer with active mitotic division. In other animal species, however, endothelial cell regenerative activity varies. In the rabbit, endothelial cell mitosis is common, and the number of corneal endothelial cells actually increases with age. 10 "" Both the cat and monkey endothelium have limited mitotic activity and respond to trauma in a manner similar to man. 12 " 13 The dog is a potentially valuable model for endothelial cell analysis. Corneal endothelial cell density decreases with age in the dog in a manner similar to man. 14 Additionally, models of primary endothelial cell (Fuchs-like) dystrophy and glaucoma associated endothelial cell disease are present in the dog but lacking in the cat and monkey. 15 " 18 To be a useful animal model, the model should behave in a manner similar to man. While the dog loses endothelial cells with age, 14 the response of these cells to surgical trauma is unknown. The purpose of this paper is to study the effect of phacoemulsification and extracapsular lens removal on endothelial cell density and corneal thickness in the dog and compare these to the responses observed in man. Materials and Methods Phacoemulsification Fourteen dogs ranging in age from 24 to 132 months were examined for cataractous lens removal /83/0200/227/$ 1. Association for Research in Vision and Ophthalmology 227

2 2 INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / Februory 1983 Vol. 24 Table 1A. Corneal endothelial cell densities before and after phacoemulsification in the dog Breed Age (mos) Phaco time (sec) Eye Preop cell density Int* days Postop cell density Cells lost (#) Cells lost (%) Cocker Terrier Terrier ' Mix % -23% -% -22% -18% -% -42% -37% -07% -02% +05% -24% -27% -24% -18% -06% -03% -13% -08% -02% -31% -25% Average % -13% * Interval days number of days between preop and postop evaluation. at the Veterinary Medical Teaching Hospital, University of Florida. All eyes were unremarkable except for the presence of mature cataracts. Following general gas anesthesia, all corneas were examined with specular microscopy immediately prior to surgery. Lenses were removed in a similar manner using an irrigation-aspiration ultrasonic instrument* and a balanced salt irrigating solutionf using two small limbal stab incisions and posterior chamber phacoemulsification. Extracapsular Lens Removal Seven dogs ranging in age from to 144 months were evaluated in a manner identical to those described for phacoemulsification. A superior limbal incision beneath a limbal-based conjunctival flap was extended 1-1. The anterior lens capsule was removed with extracapsular forceps. The lens cortex and nucleus were removed with a lens loup and minimal irrigation with a balanced salt irrigating solution.! The limbal incision and conjunctival flap were sutured with absorbable 7-0 ophthalmic suture4 * Fibra-Sonics, Chicago, IL. t BSS, Alcon Labs, Ft. Worth, TX. % Dexon, Davis and Geek. Specular Microscopy All eyes were examined with a Bio-Optics contact LSM-2000B specular microscope. A minimum of six photographs in each of three areas were taken in both central and peripheral (within 2-3 mm from the limbus) cornea. Photographs were taken immediately prior to and approximately one month following surgery (average interval: phacoemulsification: 37 days (range - days); extracapsular: days (range days). Calculations of endothelial cell density per square millimeter were standardized using a counting reticle in the photography system. An average cell count was obtained using all acceptable photographs. This included a minimum of one photo from each of three areas of central and three areas of peripheral cornea. Corneal thickness was measured with a digital pachometer within the specular microscope. A t-test analysis was used to determine the degrees of statistical significance of the change in cell density. General linear model procedures were used to determine the relationship between time of phacoemulsification and endothelial cell loss or increase in corneal thickness. Postoperative Medications All surgical cases were treated identically following surgery. All dogs received systemic ampicillin (10 mg/ Bio-Optics, Arlington, MA. Fig. 1, A-D. A, Specular microscopic appearance of central corneal endothelial cells prior to phacoemulsification of the lens in a 5-yearold dog (cell density: 19 cells/mm 2 ). B, One month after surgery; decreased cellular density, pleomorphism, and variable reflectivity of cell surfaces are present. Compare to Figure 1A (cell density: 15 cells/mm 2 ). C, A large focal endothelial cell lesion (arrows) is present one month following phacoemulsification. D, Marked cellular enlargement, pleomorphism, and cellular degeneration (arrows) one month following phacoemulsification (cell density 1120 cells/mm 2 (preop- 22 cells/mm 2 ).

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2 INVE5TIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / February 1983 Vol. 24 Phacoemulsification Results Fig. 2. Large area of central corneal edema in a 4-year-old dog 3 weeks following phacoemulsification.

4 2 INVE5TIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / February 1983 Vol. 24 Phacoemulsification Results Fig. 2. Large area of central corneal edema in a 4-year-old dog 3 weeks following phacoemulsification. kg bid), systemic prednisolone (2 mg/kg sid) in a decreasing dosage over three weeks, and topical antibiotic-corticosteroid l! and 1% Atropine sulfate, both four times daily. Anesthesia During cataract surgery, all animals were induced with sodium thiopental and maintained with Halothane gas anesthesia. For specular microscopy, a mixture of atropine (0.4 mg/kg), ketamine HC1 (10 mg/kg), and xylazine (. 1 mg/kg) was given slowly intravenously to inhibit excessive movements.!l Maxitrol, Alcon Labs, Ft. Worth, TX. The average preoperative endothelial cell counts were 22 cells/mm 2 (central) and 2244 cells/mm 2 (periphery). After surgery cell counts averaged 1748 cells/mm 2 (central) and 1950 cells/mm 2 (periphery) (Table 1A). This indicates a significant average cell loss of 22% (488 cells/mm 2 ) centrally (P < 0.001) and 13% (294 cells/mm 2 ) peripherally (P < 0.037). Specular microscopy revealed significant alterations in endothelial cell morphology. Before surgery corneal endothelial cells were of a familiar, repeating hexagonal conformation (Fig. 1A). After surgery decreased cell density, pleomorphism, and variable reflectivity of cell surfaces were noted in many cases (Fig. IB). Also, focal lesions (Fig. 1C) and areas of marked cellular degeneration (Fig. ID) were noted. Severe corneal edema, although uncommon, was also observed (Fig. 2). Phacoemulsification time was highly variable, with a range of 78 to 0 seconds. Time of phacoemulsification did not appear to be associated with the degree of endothelial cell loss (P > 0 1) (Fig. 3A). Corneal thickness increased insignificantly centrally 0.05 mm (9%) (P > 0.164) and with mild significance peripherally 0.08 mm (13%) (P < 0.012) (Table IB). There was no relationship between the degree of increased corneal thickness and the time of phacoemulsification (P > 0.1) (Fig. 3B). Table IB. Corneal thickness before and after phacoemulsification in the dog Breed Age (mos) Phaco time (sec) Eye Preop corn thickness Int* days Postop corn thickness Thickness gained Thickness gained ( c V< Cocker Terrier Terrier Mix Average % +03% 0% +08% -08% +27% + 13% +03% + 17% -17% 0% -29% +32% +% +09% +26% +06% +03% +08% +25% +27% + 14% +03% + 12% -14% + 13% * Interval days number of days between preop and postop evaluation.

5 No. 2 PHACOEMULSIFICATION AND EXTRACAPSULAR LENS REMOVAL / Gwin er ol. 231 JIM IIN-- urn- nu- m- 'UN- T H '» I ' N- Fig. 3, A,B. A, Comparison of pre- and post-operative endothelial cell density in relationship to time of phacoemulsification. B, Comparison of pre- and post-operative corneal thickness in relationship to time of phacoemulsification. IHI- A t.n- i 51 IN IM m»l 3N PHACOEMULSIFICATION TIME (SECONDS) 4M.n » * u " Vl IT * 1 * I I ' « n-.11- B IM 2N HI IN t PHACOEMULSIFICATION TIMC (SECONDS) Extracapsular Lens Removal The average preoperative endothelial cell counts were 2326 cells/mm 2 (central) and 22 cells/mm 2 (periphery). One month after surgery cell densities decreased to 1561 cells/mm 2 (central) and 1574 cells/ mm 2 (periphery) (Table 2A). Significant average endothelial cell losses of 34% (763 cells/mm 2 ) centrally (P < ) and 31% (2 cells/mm 2 ) peripherally (P < 0.003) were recorded.

6 232 INVESTIGATIVE OPHTHALMOLOGY 6 VISUAL SCIENCE / Februory 1983 Vol. 24 Table 2A. Corneal endothelial cell densities before and after extracapsular lens removal in the dog Breed Age (mos) Eye Preop cell density Int* days Postop cell density Cells lost m Cells lost (%) Schnauzer Mix % -38% -37% -34% -36% -48% -41% -43% -47% 0% -41% -22% Average % -31% Interval days number of days between preop and postop evaluation. Specular microscopy of corneal endothelial cells revealed findings similar to those seen with phacoem unification. Alterations in endothelial cell morphology varied from decreased endothelial cell density (Figs. 4A,B) to focal areas of degeneration. Specular microscopy was not performed successfully in some cases due to lack of resolution. Corneal thickness increased insignificantly centrally 0.05 mm (8%)

7 No. 2 PHACOEMULSIFICATION AND EXTRACAPSULAR LENS REMOVAL / Gwin er ol. 233 Table 2B. Corneal thickness before and after extracapsular lens removal in the dog Breed Age (mos) Eye Preop corn thickness Int* days Postop corn thickness Thickness gained Thickness gained (< Vo) Schnauzer Mix % 0% + 15% +04% +23% -21% + 17% +09% + 19% + 18% -03% + 10% + 17% Average +08% * Interval days number of days between preop and postop evaluation. (P> 0.133) and peripherally 0.08 mm (17%) (P > 0.292) (Table 2B). Scanning electron microscopy (SEM) of corneal endothelium from two cases of extracapsular lens removal demonstrated areas of bared Descemet's membrane (Fig. 5A). Evidence of endothelial cell migration was seen associated with restoration of a functional monolayer (Figs. 5B,C). Even in cases of electron microscopically verified defects in the endothelial cell layer, corneal edema and decompensation remained minimal. Discussion This study provides additional evidence that dog corneal endothelial cells behave in a similar biologic manner to man and represent a reasonable model for human corneal endothelial cell disease. Endothelial cell losses following phacoemulsification of 22% centrally and 13% peripherally correspond to cell losses observed in man. 5 " 6 Also, our study reveals an almost identical preoperative cell count in central and peripheral cornea, while postoperative cell counts show an increasing disparity between central and peripheral cornea. Similar finds have been observed in man. 19 " 20 Increased corneal thickness was also observed, as in man, and is probably related to both loss of endothelial cells and surgical trauma. Phacoemulsification time did not appear related to the degree of endothelial cell loss. This would indicate other factors are involved and that the time of ultrasonic fragmentation and duration of anterior chamber irrigation are less important. These findings are in correlation with previous studies involving the pathogenesis of endothelial cell degeneration associated with phacoemulsification. 421 Polack demonstrated that ultrasound and anterior chamber irrigation produced minimal endothelial cell pathology. 21 However, endothelial cell destruction was associated with other aspects of the surgical procedure such as needle contact, instrumentation, and manipulation of the lens nucleus in the anterior chamber. The higher percentage of cell loss seen in extracapsular lens removal when compared to phacoemulsification was not expected initially. Most studies of endothelial cell loss following cataract surgery have involved phacoemulsification, intracapsular lens removal, and intraocular lens implantation. However, anterior chamber manipulation of the lens nucleus during phacoemulsification consistently resulted in varying degrees of endothelial cell changes. 21 Extracapsular lens removal appears to produce similar, possibly more severe, endothelial cell trauma related to the lens rubbing the back of the cornea during removal and surgical manipulation of the cornea in general. The dog eye reacts markedly to extracapsular lens removal, and postoperative inflammation is much more intense than with phacoemulsification. The inflammatory response, along with the greater degree of surgical wound trauma and corneal manipulation may account for this phenomenon. Specular microscopic evaluation of normal dog corneal endothelium demonstrated morphologic characteristics similar to man. The preoperative endothelial cell counts in the range of cells/ mm 2 and similarity of central and peripheral cell counts, correlate well with studies in man After surgery specular microscopy revealed endothelial cell pathology, including cellular enlargement, increased pleomorphism, and focal degenerative changes. These changes suggest that the dog responds to surgical trauma by enlargement and migration of endothelial cells. Scanning electron microscopy further substantiated this finding with the active process

8 204 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / Februory 1980 Vol. 24

No. 2 PHACOEMUL5IFICATION AND EXTRACAPSULAR LENS REMOVAL / Gwin er ol. 2 Fig. 5, A-C. A, Posterior cornea in a dog 10 months following extracapsular lens removal.

9 No. 2 PHACOEMUL5IFICATION AND EXTRACAPSULAR LENS REMOVAL / Gwin er ol. 2 Fig. 5, A-C. A, Posterior cornea in a dog 10 months following extracapsular lens removal. Focal areas of bared Descemet's membrane (D) are still present, but areas of migrating endothelial cells are seen (arrows) (SEM, 100x). B, Higher magnification of areas seen in Figure 5A reveals migrating endothelial cells with pseudopodia (SEM, 1, 500X). C, SEM of corneal endothelium in regions adjacent to endothelial cell lesions with reformation of a complete monolayer. Nuclei (N) are more prominent and misshapen than normal (SEM, 1, 250X). of monolayer re-establishment observed following extracapsular lens removal. Severe endothelial cell damage in the dog results in persistent corneal edema, which in itself inhibits specular microscopic examination of endothelial cells. The degree of active mitoses that occurs following these procedures has not been investigated in the dog, but the clinical response parallels that seen in man. In fact, there is at least preliminary evidence that human corneal endothelial cell may be capable of mitotic activity in certain instances. 24 The relationship between postoperative interval and endothelial cell density and morphology should be examined. In an active process such as endothelial cell wound healing, time becomes a significant variable. 19 Also, it is difficult to establish a clinicopathologic correlation between endothelial cell density and morphology and corneal clarity. Further studies will be necessary to explore these pertinent questions. Key words: dog, corneal endothelium, endothelial regeneration, phacoemulsification, cataract surgery, animal model. References 1. Kelman CD: Phaco-emulsification and aspiration; a new technique of cataract removal. A preliminary report. Am J Ophthalmol 64:23, Polack FM and Sugar A: The phacoemulsification procedure. III. Corneal complications. Invest Ophthalmol Vis Sci 16:39, Benolken RM, Emery JM, and Landis DJ; Temperature profiles in the anterior chamber during phaco-emulsification. Invest Ophthalmol 13:71, McCarey BE, Polack FM, and Marshall W: The phacoemulsification procedure. I. The effect of intraocular irrigating solutions on the corneal endothelium. Invest Ophthalmol 15:449,, Irvine AR, Kratz RP, and O'Donnell JJ: Endothelial damage with phacoemulsification and intraocular lens implantation. Arch Ophthalmol :1023, Sugar J, Mitchelson J, and Kraff M: The effect of phacoemulsification on cornea] endothelial cell density. Arch Ophthalmol :446, Kraff MC, Sanders DR, and Lieberman HL: Specular microscopy in cataract and intraocular lens patients. A report of 564 cases. Arch Ophthalmol 98:1782, Laule A, Cable MIC, Hoffman CE, and Hanna C: Endothelial cell population changes of human cornea during life. Arch Ophthalmol :2031, 1978.

236 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / February 1983 Vol. 24 9. Laing RA, Sandstrom MM, Berrospi AR, and Leibowitz HM: Changes in the comeal endothelium as a function of age.

10 236 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / February 1983 Vol Laing RA, Sandstrom MM, Berrospi AR, and Leibowitz HM: Changes in the comeal endothelium as a function of age. Exp Eye Res 22:587, Von Sallmann L, Caravaggio LL, and Grimes P: Studies on the corneal endothelium of the rabbit. I. Cell division and growth. Am J Ophthalmol 51:955, Oh JO: Changes with age in the corneal endothelium of normal rabbits. Acta Ophthalmol 41:568, Van Horn DL, Sendele DD, Seideman S, and Buco PJ: Regenerative capacity of the corneal endothelium in rabbit and cat. Invest Ophthalmol Vis Sci 16:597, Van Horn DL and Hyndiuk RA: Endothelial wound repair in primate cornea. Exp Eye Res 21:113, Gwin RM, Lerner I, Warren JK, and Gum G: Decrease in canine corneal endothelial cell density and increase in corneal thickness as functions of age. Invest Ophthalmol Vis Sci 22:267, Dice PF and Martin CL: Corneal endothelial-epithelial dystrophy in the dog. Proc Am Coll Vet Ophthalmol 5:36, 1976; Also: J Am Anim Hosp Assoc 18:327, Gwin RM, Polack FM, Warren JK, Samuelson DA, and Gelatt KN: Primary canine corneal endothelial cell dystrophy: specular microscopic evaluation, diagnosis and therapy. J Am Anim Hosp Assoc 18:471, Gelatt KN, Peiffer RL Jr, Gwin RM, and Sauk JJ Jr: Glaucoma in the beagle. Trans Am Acad Ophthalmol Otolaryngol 81:636, Gwin RM, Warren JK, and Gelatt KN: Effect of chronic openangle glaucoma on endothelial cell density and corneal thickness in the beagle. Unpublished data, Rao GN, Shaw EL, Arthur E, and Aquavella JV: Morphological appearance of the healing corneal endothelium. Arch Ophthalmol :2027, Hoffer KJ: Vertical endothelial cell disparity. Am J Ophthalmol 87:344, Polack FM and Sugar A: The phacoemulsification procedure. II. Corneal endothelial changes. Invest Ophthalmol 15:458, Blackwell WL, Gravenstein N, and Kaufman HE: Comparison of central corneal endothelial cell numbers with peripheral areas. Am J Ophthalmol 84:473, Sturrock GD, Sherrard ES, and Rice NSC: Specular microscopy of the corneal endothelium. Br J Ophthalmol 62:809, Treffers WF: Human corneal endothelial wound healing in organ culture and autoradiography. ARVO Abstracts. Invest Ophthalmol Vis Sci 20(Suppl): 2, 1981; Also: Ophthalmology 89:5, 1982.

The phacoemulsification procedure. II. Corneal endothelial changes. Frank M. Polack and Alan Sugar*

The phacoemulsification procedure. II. Corneal endothelial changes Frank M. Polack and Alan Sugar* The effect of phacoemulsification, with the Cavitron-Kelman instrument, on the corneal endothelium of