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Corneal Endothelial Response to Corticosteroid in Cataract Surgery
Corneal Endothelial Response to Corticosteroid in Cataract Surgery KEVIN EVANS, COlM O'BRIEN and ALAN PATTERSON St Paul's Eye Unit, Royal Liverpool University Hospital, Prescot Street, Liverpool, L78XP, UK
OBJECTIVE: To assess the influence of enhanced corticosteroid therapy on long term corneal endothelial cell survival after extracapsular cataract surgery. STUDY DESIGN: A one-year, randomized, prospective double-blind study. SETTING: Teaching hospital, St. Paul's Eye Unit, Liverpool. PATIENTS: Thirty-four subjects undergoing cataract surgery were randomly assigned to either conventional management or in addition to receive 20 mg subconjunctival depo-methylprednisolone acetate at the end of the procedure. MAIN OUTCOME MEASURES: Mean endothelial cell loss, coefficient of variation in cell area and deviation from hexagonality. RESULTS: Mean cell loss was significantly less in the depo-corticosteroid treated group at three months but this was associated with an increase in cell polymegathism and pleomorphism. At 12 months mean cell loss was significantly greater. CONCLUSIONS: It is proposed that corticosteroid inhibits endothelial cell motility, handicapping long term repair. Enhanced corticosteroid may therefore be deleterious to endothelial survival after cataract surgery and should be avoided especially when low cell counts have been found pre-operatively. Keywords: Cataract surgery; Corneal endothelium; Corticosteroid.
INTRODUCTION
A lot of effort has been expended on improving endothelial survival in cataract surgery so as to avoid potentially sight-threatening complications such as bullous keratopathy and permanent corneal scarring. Improved surgical techniques, better instrumentation and the use of viscoelastic materials have all helped to improve the situation. However recent prospective studies have suggested that significant endothelial cell loss still occurs and continues for years after surgery [1, 2]. For example, Liesegang et al. [3] have shown enhanced endothelial cell loss for at least 2 years following extracapsular cataract extraction with posterior chamber lens implantation. Chronic, low grade anterior segment inflammation has been proposed as one possible cause for this continuing damage [4] and has been documented to be present for at least three months post-operatively using anterior chamber fluorophotometry [4] and for 6 months using a laser flare-cell meter [5]. Correspondence and reprint requests to: K. Evans, Institute of Ophthalmology, Bath Street, London, ECIV 9EL, UK.
Corticosteroids have been used for many years to combat anterior segment inflammation, the level of response being dependent on dose and type of corticosteroid used [6]. Therefore it was proposed that if anterior segment inflammation coritributed significantly to continuing endothelial loss after cataract surgery, enhanced steroid therapy (beyond that usually prescribed) should diminish this loss. Sihce anterior segment inflammation is most apparent up to three months post-operatively [4] enhanced steroid therapy during this period should produce a measurable improvement in endothelial survival. To investigate this proposal, a prospective randomized study of patients undergoing routine extracapsular cataract surgery was undertaken. Corneal endothelial damage in those receiving conventional corticosteroid treatment as part of their post-operative management were compared with those who received enhanced corticosteroid therapy. METHODS
Local Ethical committee approval was obtained to study patients undergoing conventional, routine
0955-3681/94/020074+05 $08.00/0 © 1994 W.B. Saunders Company Limited
Eur J Implant Ref Surg, Vol 6, April 1994
75
Corneal Endothelial Response to Corticosteroid in Cataract Surgery
extracapsular cataract extraction with insertion of a posterior chamber intraocular lens. Informed consent was obtained from all subjects who took part. Patients with other ophthalmic pathologies apart from cataract or general medical conditions known to affect the corneal endothelium, e.g. diabetes mellitus, were excluded. Subjects who had undergone systemic steroid therapy within the last six months were also excluded. Subjects were randomly assigned to either undergo conventional cataract surgery management including post-operative corticosteroid drops (Group A), or in addition to receive a subconjunctival injection of depo-methylprednisolone acetate (Depo-MedroD at the end of the procedure (Group B). Randomization was achieved by using a table of random numbers [7] and allocations were made prior to surgery and not revealed to the surgeon until the procedure was completed. All surgery was performed by two surgeons using identical techniques. Anterior chamber access was gained via a bevelled corneal incision extending for five clock hours. A viscoelastic was used to maintain anterior chamber depth. Extracapsular extraction was achieved using a can-opener capsulotomy, nuclear expression and cortical removal with an irrigation/aspiration cannula. A PMMA posterior chamber lens was positioned within the capsular bag, viscoelastic removed by aspiration and irrigation with saline and the cornea sutured with continuous 10/0 silk. At this point those selected received a subconjunctival injection of 20 mg de pomethylprednisolone acetate at the 12 o'clock position. Post-operatively all subjects received topical guttae prednisolone acetate on a reducing dose for three months and topical guttae cyclopentolate 1% for two weeks following surgery. Patients underwent anterior segment examination and tonometry on the day following surgery and at two and six weeks and three, six and 12 months post-operatively. Corneal endothelial images were obtained using a contact specular microscope (Keeler-Konan). These were recorded with a dedicated U-Matic video recorder. Specular microscopy was performed on the day prior to surgery and at the three, six and 12 month post-operative visits. The four clearest images from inferior, central and superior corneal endothelium were chosen from each examination session for further analysis. Upper endothelial images were obtained as close to the corneal section as possible. All specular microscopy was undertaken without the examiner knowing the clinical status of the patient. Endothelial images were analysed using a modified Joyce-Lobel mini-magiscan image analyser [8]. Data from the four different images from each cor-
neal zone was combined to more accurately represent that zone. The image analyser generated information on cell numbers per selected video frame, individual cell areas and cell perimeters. This information was exported to a 486 DX2 microprocessor. Using a spreadsheet program, cell densities were calculated. Using a method described by Bates et al. [9], cell areas and perimeters were used to quantify cell morphology. Polymegathism was calculated as the coefficient of variation in cell area. Pleomorphism was calculated as deviation from hexagonality such that if a cell was a perfect equilateral hexagon, the value for deviation from hexagonality would be 100. The mean values for cell densities, coefficients of variation in cell areas and deviations from hexagonality in Groups A and B were compared statistically using two sample t-tests and confidence intervals calculated. RESULTS
Thirty-six eyes of 36 patients constituted the study population. Nineteen were randomly allocated to Group A and 17 to Group B. Two patients, one from each group, were excluded from analysis due to postsurgical complications (late iris prolapse in both cases). Group A were therefore finally composed of 18 patients with an average age of 64 years (range 45-71), of which 10 were female. Group B composed 16 patients with an average age of 62 years (range 50-72) and seven were female. Surgeon 1 operated on eight patients in Group A and seven in Group B. Surgeon 2 operated on 10 patients in Group A and nine in Group B. Mean values for corneal endothelial indices for each group are presented in Fig. 1 (cell densities), Table 1 (coefficients of variation in cell areas) and Table 2 (deviation from hexagonality). No statistically significant difference in endothelial indices was found pre-operatively. Differences were however noted post-operatively between the two groups. Average mean percentage cell loss was significantly less in Group B three months after surgery (t = 8.1,95% confidence interval (95%CI) = 4.3-7.4 for estimates of upper corneal cell densities and t = 4.2, 95%CI = 1.0-3.2 for the central corneal zone). In contrast, average mean percentage cell loss for Group B were significantly greater at 12 months for both upper (t = 5.1, 95%CI = 2.0-4.9) and central endothelial zones (t = 4.9, 95%CI = 1.8-4.6). Differences at six months were not significant. Differences in the post-operative mean values for the indices of polymegathism and polymorphism were also found. For upper and central corneal endothelial zones, the mean coefficients of variation in cell Eur J Implant Ref Surg, Vol 6, April 1994
K. Evans et al.
76
Cell loss, %
25
I
----
20
I
Upper corneal zone
----
I
I
_------1
15
Central corneal zone
10
--- --- ---
5
Lower corneal zone
o surgery
3 months
6 months
I year
Time from surgery
Fig. I. Percentage endothelial cell loss from superior, central and lower corneal zones. Values given are mean ± standard deviation. - - , Group A; - - - -, Group B. Table I Change in coefficient of variation in endothelial cell area of the upper and central corneal zones. Mean ± standard deviation Group A Group B Pre-operative 3 months 6 months 1 year
Upper zone 31.1 (l.4) 32.8 (1.6) 32.0 (1.2) 31. 7 (2.5)
Central zone 30.5 (2.7) 29.6 (2.2) 30.0 (l.9) 31.1 (1.4)
Upper zone 32.0 (l.9) 35.1 (1.5) 32.5 (2.4) 31.9 (1.3)
Central zone 31.0 (2.0) 32.6 (0.8) 31.0 (2.8) 31.4 n.8)
Table 2 Change in deviation from hexagonality of endothelial cells for upper and central corneal zones. Mean ± standard deviation Group A Group B Pre-operative 3 months 6 months 1 year
Upper zone 93.6 (1.9) 92.5 (1.3) 92.0 (1.1) 93.0 (1.5)
Central zone 93.4 (2.1) 90.4 (0.7) 93.0 (0.9) 93.1 (1.1)
Upper zone 93.1 (0.9) 91.2 (0.9) 90.5 (2.1) 91.0 (2.3)
Central zone 93.2 (2.0) 89.2 (1.1) 92.0 (2.5) 93.0 (2.0)
area for group B were significantly greater than for group A at three months (t = 3.6, 95%CI = 1.1-4.8 for upper and t = 3.1, 95%CI = 4.9-8.5 for central corneal zones). Mean values for deviation from hexagonality were also significantly different at three months (t = 4.1, 95%CI = 0.9-3.0 for upper and t = 3.75, 95%CI = 0.8-3.2 for central corneal zones, respectively). No differences in mean endothelial Eur J Implant Ref Surg, Vol 6, April 1994
indices were found at three, six or 12 months for lower corneal zones in groups A and B. DISCUSSION
Despite this being a small study, statistically significant differences in corneal endothelial cell indices were seen between groups A and B at three and 12 months and it seems reasonable to assume that this was due to the additional procedure. The beneficial reduction in cell loss that was theoretically expected with subconjunctival depo-methylprednisolone acetate was seen at three months but had been lost by six months and developed into an increased loss by 12 months. Depo-methylprednisolone acetate is reported to be a potent steroid which when given subconjunctivally will release steroid to orbital tissues for at least four weeks [6]. Prolonged activity is thought to be due to combination of the drug with various acetates which are degraded over different time intervals releasing the active methyl prednisolone over an extended period, [10]. However, most studies on the kinetics of subconjunctival steroid preparations have been based either on animal or normal human eyes [11, 12]. It has recently been shown that there are significant differences between animal and human ocular steroid pharmacokinetics [13]. Also, McCartey et al. [14] has shown drug penetration in inflamed eyes to be better than
Corneal Endothelial Response to Corticosteroid in Cataract Surgery
in normal human eyes. Therefore although corticosteroid has been found in monkey eyes for weeks following subconjunctival depo-methylprednisolone acetate injection [15], this has yet to be established in human post-operative eyes. The present study does suggest however that anterior segment penetration in humans is sufficient to enhance levels of corticosteroid and for a long enough period to directly influence corneal endothelial morphology for at least three months. Possibly this may be a toxic response to the preservative in the proprietary depo-methylprednisolone acetate used in this study (Depo-Medrol). Loewenstein et al. [16] have shown that the preservative used (myristyl-gamma-picolinium chloride, MGP) can be toxic to ocular tissues. However this is unlikely to be the cause of the adverse endothelial response seen in this study since toxic effects to this preservative have only been seen to date when the drug has been injected intra-ocularly. These adverse effects are also thought to be mediated via an enhanced inflammatory response which would have been identified during the follow-up examinations. There have been few accounts of the effects of corticosteroid on corneal endothelial wound healing and no human studies have been reported. Sanchez and Polack [17] looked at endothelial wound healing after cryocautery in the adult rabbit. They found that topical dexamethasone retarded but did not stop endothelial healing and that this response was due to a reduction in mitotic rate. Yamaguchi et al. [18] found that subconjunctival methylprednisolone acetate conferred no long-term benefits in terms of numbers of corneal endothelial cells after anterior radial keratotomy in the green monkey. More recently, Belkin et al. [19] have found an increase in the mean coefficient of variation in cell area and fewer hexagonal cells in the traumatized corneal endothelial cells of the cat eye following retrobulbar betamethasone sodium phosphate. However the study period only extended to seven days post-injury and may not reflect long term abnormalities. In our study significant long term effects have been seen. Initially, increased cell densities and pleomorphism in the upper and central endothelial cell layer at three months was thought to suggest a preservation of cells but may actually represent an inhibition of spread of endothelial cells to cover exposed areas of Descemets' membrane. Significantly reduced cell densities at 12 months in Group B confirm the longterm adverse response to corticosteroid. It is unlikely that significant amounts of corticosteroid were present in ocular tissues beyond three months which suggests that a delay or handicapping of healing occurs within the first 12 weeks of reparation which is sufficiently profound to impair long-
77
term recovery. Corticosteroids are known to affect lipid metabolism which theoretically could alter the phospholipid content of cell membranes altering cell fluidity and rigidity [20] and thus inhibit mobility. This mechanism may explain the increased cell pleomorphism also seen at three months. In addition, humoral inflammatory mediators are known to affect corneal endothelial motility [21]. Although no significant difference in anterior segment inflammation was seen between the two groups on clinical examination, a difference may have been apparent if inflammation had been assessed more critically, e.g. by assessing the blood ocular barrier using a flarecell meter or by anterior chamber fluorophotometry. By modifying the inflammatory response depomethylprednisolone acetate may have inhibited endothelial cell spread and repair of defects in the endothelial monolayer. Overall we propose that these results suggest an improvement in short-term endothelial survival with subconjunctival depomethylprednisolone acetate. However post-operative endothelial repair is handicapped to such an extent that this advantage is reversed by 12 months. This may have less significance in corneas with high endothelial cell counts, but may be sufficient to lead to permanent corneal decompensation when cell counts are low, e.g. in the aged eye or in those who have undergone previous anterior segment surgery or trauma. In conclusion, subconjunctival depo-methylprednisolone acetate has been shown to adversely influence long term corneal endothelial wound healing following uncomplicated extracapsular cataract surgery. This suggests that it (and possibly other long acting steroid preparations) be avoided in routine cataract surgery especially if low endothelial cell counts have been found pre-operatively.
REFERENCES 1 Oxford Cataract Treatment and Evaluation Team (OCTET). Long-term corneal endothelial cell loss after cataract surgery. Results of a randomized controlled trial. Arch. Ophthalmol., 1986; 104: 1170-1175. 2 M Matsuda, K Miyake, M Inaba. Long-term corneal endothelial changes after intraocular lens implantation. Am. J . Ophthalmol., 1988; 105: 248-252. 3 TJ Liesegang, WM Bourne, DM Ilstrup. Short- and long-term endothelial cell loss associated with cataract extraction and intraocular lens implantation. Am. J. Ophthalmol., 1984; 97: 32-39. 4 VMG Feguson, DJ Spalton. Continued breakdown of the blood aqueous barrier following cataract surgery. Br. J. Ophthalmol., 1992; 76: 453-456. 5 T Osia, K Yoshimura, N Miyata. Postsurgical inflammation after phacoemulsification and extracapsular extraction with soft or conventional intraocular lens implantation. J. Cataract Refract. Surg., 1992; 18: 356-361. 6 WH Havener. Ocular Pharmacology. Fifth Edition. CV Mosby, St. Louis, 1983: 456. Eur J Implant Ref Surg, Vol 6, April 1994
78 7 A Pere. Lecture notes on Medical Statistics. Second Edition. Blackwell, Oxford, 1987: 191-195. 8 JA Hunt, DG Vince, DF Williams. Image analysis in the evaluation ofbiomaterials. J. Biomed. Engineering, 1993; 15: 39-45. 9 AK Bates, H Cheng. Bullous keratopathy: a study of endothelial cell morphology in patients undergoing cataract surgery. Br. J. Ophthalmol., 1988; 72: 409-412. 10 RS Coles, DL Krohn, H Breslin. Depo-Medrol in the treatment of inflammatory diseases of the anterior segment ofthe eye. Am. J. Ophthalmol., 1962; 54: 407. 11 N Wine, AG Gornall PK Basu. The ocular uptake of subconjunctivally injected 14C hydrocortisone. Am. J. Ophthalmol., 1964; 58: 362-366. 12 MR Jain, S Srivastava. Ocular penetration of hydrocortisone and dexamethasone into the aqueous humor after subconjunctival injection. Trans. Ophthal. Soc. U.K, 1978; 98: 63-65. 13 DM Maurice, Y Ota. The kinetics of subconjunctival injections. Jpn. J. Ophthalmol., 1978; 22: 95-100. 14 HJ McCartney, 10 Drysdale, AG Gornall, PK Basu. An autoradiographic study of the penetration of subconjunctivally injected hydrocortisone into normal and inflamed
Eur J Implant Ref Surg, Vol 6, April 1994
K. Evans
et sl.
rabbit eye. Invest. Ophthalmol. Vis. Sci., 1965; 4: 297-299. 15 RA Hyndiuk, MG Reagan. Radioactiv~ depot-corticosteroid penetration into monkey ocular tissue. Arch. Ophthalmol., 1968; 80: 499-503. 16 A Loewestein, E Zemel, M Lazar, I Perlman. The effects of Depo-Medrol preservative on the rabbit visual system. Invest. Ophthalmol. Vis. Sci., 1991; 32: 3053-3060. 17 J Sanchez, FM Polack. Effect of topical steroids on the healing of corneal endothelium. Invest. Ophthalmol., 1974; 13: 17-2l. 18 T Yamaguchi, PA Asbell, M Ostrick, GE Kissling, A Safir, HE Kaufman. Corticosteroid therapy after anterior radial keratotomy in primates. Am. J. Ophthalmol., 1984; 97: 215-220. 19 M Belkin, A Solomon, N Landshman. The effect of corticosteroids on the healing of corneal endothelium in cats. Invest. Ophthalmol. Vis. Sci., (ARVO abstracts), 1993; 34: 1195. 20 EM Mahoney, WA Scott,FR Landsberger. Influence of fatty acyl substitution on the composition and function of macrophage membranes. J. Bio!. Chem., 1980; 255: 4910-4917. 21 NC Joyce, B Meklir. Protein kinase C activation during corneal endothelial wound healing. Invest. Ophthalmol. Vis. Sci., 1992; 33: 1958-1973.
OBJECTIVE: To assess the influence of enhanced corticosteroid therapy on long term corneal endothelial cell survival after extracapsular cataract surgery. STUDY DESIGN: A one-year, randomized, prospective double-blind study. SETTING: Teaching hospital, St. Paul's Eye Unit, Liverpool. PATIENTS: Thirty-four subjects undergoing cataract surgery were randomly assigned to either conventional management or in addition to receive 20 mg subconjunctival depo-methylprednisolone acetate at the end of the procedure. MAIN OUTCOME MEASURES: Mean endothelial cell loss, coefficient of variation in cell area and deviation from hexagonality. RESULTS: Mean cell loss was significantly less in the depo-corticosteroid treated group at three months but this was associated with an increase in cell polymegathism and pleomorphism. At 12 months mean cell loss was significantly greater. CONCLUSIONS: It is proposed that corticosteroid inhibits endothelial cell motility, handicapping long term repair. Enhanced corticosteroid may therefore be deleterious to endothelial survival after cataract surgery and should be avoided especially when low cell counts have been found pre-operatively. Keywords: Cataract surgery; Corneal endothelium; Corticosteroid.
INTRODUCTION
A lot of effort has been expended on improving endothelial survival in cataract surgery so as to avoid potentially sight-threatening complications such as bullous keratopathy and permanent corneal scarring. Improved surgical techniques, better instrumentation and the use of viscoelastic materials have all helped to improve the situation. However recent prospective studies have suggested that significant endothelial cell loss still occurs and continues for years after surgery [1, 2]. For example, Liesegang et al. [3] have shown enhanced endothelial cell loss for at least 2 years following extracapsular cataract extraction with posterior chamber lens implantation. Chronic, low grade anterior segment inflammation has been proposed as one possible cause for this continuing damage [4] and has been documented to be present for at least three months post-operatively using anterior chamber fluorophotometry [4] and for 6 months using a laser flare-cell meter [5]. Correspondence and reprint requests to: K. Evans, Institute of Ophthalmology, Bath Street, London, ECIV 9EL, UK.
Corticosteroids have been used for many years to combat anterior segment inflammation, the level of response being dependent on dose and type of corticosteroid used [6]. Therefore it was proposed that if anterior segment inflammation coritributed significantly to continuing endothelial loss after cataract surgery, enhanced steroid therapy (beyond that usually prescribed) should diminish this loss. Sihce anterior segment inflammation is most apparent up to three months post-operatively [4] enhanced steroid therapy during this period should produce a measurable improvement in endothelial survival. To investigate this proposal, a prospective randomized study of patients undergoing routine extracapsular cataract surgery was undertaken. Corneal endothelial damage in those receiving conventional corticosteroid treatment as part of their post-operative management were compared with those who received enhanced corticosteroid therapy. METHODS
Local Ethical committee approval was obtained to study patients undergoing conventional, routine
0955-3681/94/020074+05 $08.00/0 © 1994 W.B. Saunders Company Limited
Eur J Implant Ref Surg, Vol 6, April 1994
75
Corneal Endothelial Response to Corticosteroid in Cataract Surgery
extracapsular cataract extraction with insertion of a posterior chamber intraocular lens. Informed consent was obtained from all subjects who took part. Patients with other ophthalmic pathologies apart from cataract or general medical conditions known to affect the corneal endothelium, e.g. diabetes mellitus, were excluded. Subjects who had undergone systemic steroid therapy within the last six months were also excluded. Subjects were randomly assigned to either undergo conventional cataract surgery management including post-operative corticosteroid drops (Group A), or in addition to receive a subconjunctival injection of depo-methylprednisolone acetate (Depo-MedroD at the end of the procedure (Group B). Randomization was achieved by using a table of random numbers [7] and allocations were made prior to surgery and not revealed to the surgeon until the procedure was completed. All surgery was performed by two surgeons using identical techniques. Anterior chamber access was gained via a bevelled corneal incision extending for five clock hours. A viscoelastic was used to maintain anterior chamber depth. Extracapsular extraction was achieved using a can-opener capsulotomy, nuclear expression and cortical removal with an irrigation/aspiration cannula. A PMMA posterior chamber lens was positioned within the capsular bag, viscoelastic removed by aspiration and irrigation with saline and the cornea sutured with continuous 10/0 silk. At this point those selected received a subconjunctival injection of 20 mg de pomethylprednisolone acetate at the 12 o'clock position. Post-operatively all subjects received topical guttae prednisolone acetate on a reducing dose for three months and topical guttae cyclopentolate 1% for two weeks following surgery. Patients underwent anterior segment examination and tonometry on the day following surgery and at two and six weeks and three, six and 12 months post-operatively. Corneal endothelial images were obtained using a contact specular microscope (Keeler-Konan). These were recorded with a dedicated U-Matic video recorder. Specular microscopy was performed on the day prior to surgery and at the three, six and 12 month post-operative visits. The four clearest images from inferior, central and superior corneal endothelium were chosen from each examination session for further analysis. Upper endothelial images were obtained as close to the corneal section as possible. All specular microscopy was undertaken without the examiner knowing the clinical status of the patient. Endothelial images were analysed using a modified Joyce-Lobel mini-magiscan image analyser [8]. Data from the four different images from each cor-
neal zone was combined to more accurately represent that zone. The image analyser generated information on cell numbers per selected video frame, individual cell areas and cell perimeters. This information was exported to a 486 DX2 microprocessor. Using a spreadsheet program, cell densities were calculated. Using a method described by Bates et al. [9], cell areas and perimeters were used to quantify cell morphology. Polymegathism was calculated as the coefficient of variation in cell area. Pleomorphism was calculated as deviation from hexagonality such that if a cell was a perfect equilateral hexagon, the value for deviation from hexagonality would be 100. The mean values for cell densities, coefficients of variation in cell areas and deviations from hexagonality in Groups A and B were compared statistically using two sample t-tests and confidence intervals calculated. RESULTS
Thirty-six eyes of 36 patients constituted the study population. Nineteen were randomly allocated to Group A and 17 to Group B. Two patients, one from each group, were excluded from analysis due to postsurgical complications (late iris prolapse in both cases). Group A were therefore finally composed of 18 patients with an average age of 64 years (range 45-71), of which 10 were female. Group B composed 16 patients with an average age of 62 years (range 50-72) and seven were female. Surgeon 1 operated on eight patients in Group A and seven in Group B. Surgeon 2 operated on 10 patients in Group A and nine in Group B. Mean values for corneal endothelial indices for each group are presented in Fig. 1 (cell densities), Table 1 (coefficients of variation in cell areas) and Table 2 (deviation from hexagonality). No statistically significant difference in endothelial indices was found pre-operatively. Differences were however noted post-operatively between the two groups. Average mean percentage cell loss was significantly less in Group B three months after surgery (t = 8.1,95% confidence interval (95%CI) = 4.3-7.4 for estimates of upper corneal cell densities and t = 4.2, 95%CI = 1.0-3.2 for the central corneal zone). In contrast, average mean percentage cell loss for Group B were significantly greater at 12 months for both upper (t = 5.1, 95%CI = 2.0-4.9) and central endothelial zones (t = 4.9, 95%CI = 1.8-4.6). Differences at six months were not significant. Differences in the post-operative mean values for the indices of polymegathism and polymorphism were also found. For upper and central corneal endothelial zones, the mean coefficients of variation in cell Eur J Implant Ref Surg, Vol 6, April 1994
K. Evans et al.
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Cell loss, %
25
I
----
20
I
Upper corneal zone
----
I
I
_------1
15
Central corneal zone
10
--- --- ---
5
Lower corneal zone
o surgery
3 months
6 months
I year
Time from surgery
Fig. I. Percentage endothelial cell loss from superior, central and lower corneal zones. Values given are mean ± standard deviation. - - , Group A; - - - -, Group B. Table I Change in coefficient of variation in endothelial cell area of the upper and central corneal zones. Mean ± standard deviation Group A Group B Pre-operative 3 months 6 months 1 year
Upper zone 31.1 (l.4) 32.8 (1.6) 32.0 (1.2) 31. 7 (2.5)
Central zone 30.5 (2.7) 29.6 (2.2) 30.0 (l.9) 31.1 (1.4)
Upper zone 32.0 (l.9) 35.1 (1.5) 32.5 (2.4) 31.9 (1.3)
Central zone 31.0 (2.0) 32.6 (0.8) 31.0 (2.8) 31.4 n.8)
Table 2 Change in deviation from hexagonality of endothelial cells for upper and central corneal zones. Mean ± standard deviation Group A Group B Pre-operative 3 months 6 months 1 year
Upper zone 93.6 (1.9) 92.5 (1.3) 92.0 (1.1) 93.0 (1.5)
Central zone 93.4 (2.1) 90.4 (0.7) 93.0 (0.9) 93.1 (1.1)
Upper zone 93.1 (0.9) 91.2 (0.9) 90.5 (2.1) 91.0 (2.3)
Central zone 93.2 (2.0) 89.2 (1.1) 92.0 (2.5) 93.0 (2.0)
area for group B were significantly greater than for group A at three months (t = 3.6, 95%CI = 1.1-4.8 for upper and t = 3.1, 95%CI = 4.9-8.5 for central corneal zones). Mean values for deviation from hexagonality were also significantly different at three months (t = 4.1, 95%CI = 0.9-3.0 for upper and t = 3.75, 95%CI = 0.8-3.2 for central corneal zones, respectively). No differences in mean endothelial Eur J Implant Ref Surg, Vol 6, April 1994
indices were found at three, six or 12 months for lower corneal zones in groups A and B. DISCUSSION
Despite this being a small study, statistically significant differences in corneal endothelial cell indices were seen between groups A and B at three and 12 months and it seems reasonable to assume that this was due to the additional procedure. The beneficial reduction in cell loss that was theoretically expected with subconjunctival depo-methylprednisolone acetate was seen at three months but had been lost by six months and developed into an increased loss by 12 months. Depo-methylprednisolone acetate is reported to be a potent steroid which when given subconjunctivally will release steroid to orbital tissues for at least four weeks [6]. Prolonged activity is thought to be due to combination of the drug with various acetates which are degraded over different time intervals releasing the active methyl prednisolone over an extended period, [10]. However, most studies on the kinetics of subconjunctival steroid preparations have been based either on animal or normal human eyes [11, 12]. It has recently been shown that there are significant differences between animal and human ocular steroid pharmacokinetics [13]. Also, McCartey et al. [14] has shown drug penetration in inflamed eyes to be better than
Corneal Endothelial Response to Corticosteroid in Cataract Surgery
in normal human eyes. Therefore although corticosteroid has been found in monkey eyes for weeks following subconjunctival depo-methylprednisolone acetate injection [15], this has yet to be established in human post-operative eyes. The present study does suggest however that anterior segment penetration in humans is sufficient to enhance levels of corticosteroid and for a long enough period to directly influence corneal endothelial morphology for at least three months. Possibly this may be a toxic response to the preservative in the proprietary depo-methylprednisolone acetate used in this study (Depo-Medrol). Loewenstein et al. [16] have shown that the preservative used (myristyl-gamma-picolinium chloride, MGP) can be toxic to ocular tissues. However this is unlikely to be the cause of the adverse endothelial response seen in this study since toxic effects to this preservative have only been seen to date when the drug has been injected intra-ocularly. These adverse effects are also thought to be mediated via an enhanced inflammatory response which would have been identified during the follow-up examinations. There have been few accounts of the effects of corticosteroid on corneal endothelial wound healing and no human studies have been reported. Sanchez and Polack [17] looked at endothelial wound healing after cryocautery in the adult rabbit. They found that topical dexamethasone retarded but did not stop endothelial healing and that this response was due to a reduction in mitotic rate. Yamaguchi et al. [18] found that subconjunctival methylprednisolone acetate conferred no long-term benefits in terms of numbers of corneal endothelial cells after anterior radial keratotomy in the green monkey. More recently, Belkin et al. [19] have found an increase in the mean coefficient of variation in cell area and fewer hexagonal cells in the traumatized corneal endothelial cells of the cat eye following retrobulbar betamethasone sodium phosphate. However the study period only extended to seven days post-injury and may not reflect long term abnormalities. In our study significant long term effects have been seen. Initially, increased cell densities and pleomorphism in the upper and central endothelial cell layer at three months was thought to suggest a preservation of cells but may actually represent an inhibition of spread of endothelial cells to cover exposed areas of Descemets' membrane. Significantly reduced cell densities at 12 months in Group B confirm the longterm adverse response to corticosteroid. It is unlikely that significant amounts of corticosteroid were present in ocular tissues beyond three months which suggests that a delay or handicapping of healing occurs within the first 12 weeks of reparation which is sufficiently profound to impair long-
77
term recovery. Corticosteroids are known to affect lipid metabolism which theoretically could alter the phospholipid content of cell membranes altering cell fluidity and rigidity [20] and thus inhibit mobility. This mechanism may explain the increased cell pleomorphism also seen at three months. In addition, humoral inflammatory mediators are known to affect corneal endothelial motility [21]. Although no significant difference in anterior segment inflammation was seen between the two groups on clinical examination, a difference may have been apparent if inflammation had been assessed more critically, e.g. by assessing the blood ocular barrier using a flarecell meter or by anterior chamber fluorophotometry. By modifying the inflammatory response depomethylprednisolone acetate may have inhibited endothelial cell spread and repair of defects in the endothelial monolayer. Overall we propose that these results suggest an improvement in short-term endothelial survival with subconjunctival depomethylprednisolone acetate. However post-operative endothelial repair is handicapped to such an extent that this advantage is reversed by 12 months. This may have less significance in corneas with high endothelial cell counts, but may be sufficient to lead to permanent corneal decompensation when cell counts are low, e.g. in the aged eye or in those who have undergone previous anterior segment surgery or trauma. In conclusion, subconjunctival depo-methylprednisolone acetate has been shown to adversely influence long term corneal endothelial wound healing following uncomplicated extracapsular cataract surgery. This suggests that it (and possibly other long acting steroid preparations) be avoided in routine cataract surgery especially if low endothelial cell counts have been found pre-operatively.
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78 7 A Pere. Lecture notes on Medical Statistics. Second Edition. Blackwell, Oxford, 1987: 191-195. 8 JA Hunt, DG Vince, DF Williams. Image analysis in the evaluation ofbiomaterials. J. Biomed. Engineering, 1993; 15: 39-45. 9 AK Bates, H Cheng. Bullous keratopathy: a study of endothelial cell morphology in patients undergoing cataract surgery. Br. J. Ophthalmol., 1988; 72: 409-412. 10 RS Coles, DL Krohn, H Breslin. Depo-Medrol in the treatment of inflammatory diseases of the anterior segment ofthe eye. Am. J. Ophthalmol., 1962; 54: 407. 11 N Wine, AG Gornall PK Basu. The ocular uptake of subconjunctivally injected 14C hydrocortisone. Am. J. Ophthalmol., 1964; 58: 362-366. 12 MR Jain, S Srivastava. Ocular penetration of hydrocortisone and dexamethasone into the aqueous humor after subconjunctival injection. Trans. Ophthal. Soc. U.K, 1978; 98: 63-65. 13 DM Maurice, Y Ota. The kinetics of subconjunctival injections. Jpn. J. Ophthalmol., 1978; 22: 95-100. 14 HJ McCartney, 10 Drysdale, AG Gornall, PK Basu. An autoradiographic study of the penetration of subconjunctivally injected hydrocortisone into normal and inflamed
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