Intraoperative mitomycin C and the corneal endothelium
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A O S 1998
Intraoperative mitomycin C andthe corneal endotheliumR. Sihota, Tarun Sharma and H. C. Agarwal
Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of MedicalSciences, New Delhi, India
ABSTRACT.Purpose: Mitomycin-C (MMC) is a useful adjunct to high risk glaucomasurgery. No clinical data regarding the deleterious effect of mitomycin-C on thecorneal endothelial cells are available.Methods: Thirty eyes of 28 adult patients with high risk glaucomas were ran-domized to three groups. Group-I underwent a trabeculectomy alone, Group II,trabeculectomy with intraoperative 0.2mg/ml MMC and Group III, trabeculec-tomy with intraoperative 0.4mg/ml MMC. Preoperative and 3-month postopera-tive corneal endothelial cell counts were analysed.Results: The percentage cell loss in Group I was 3.732.73%, in Group II13.904.69% and in Group III 14.527.8%. Statistical analysis revealed asignificant difference in cell loss between Group I and Group II and Group Iand Group III, but not between Group II and Group III.Conclusion: There is a significant loss of corneal endothelial cells three monthsafter trabeculectomy with adjunctive MMC.
Key words: mitomycin-C trabeculectomy corneal endothelium cell loss intra-operative.
Acta Ophthalmol. Scand. 1998: 76: 8082Copyright c Acta Ophthalmol Scand 1998. ISSN 1395-3907
The intraoperative usefulness of mito-mycin C (MMC) is now estab-lished, especially for recalcitrant glau-comas. The initial enthusiasm has beentempered by the relatively high incidenceof thin blebs, hypotony, and choroidaldetachments noted by Kitazawa et al.(1993), Wise (1993) and Shields et al.(1993). The long term effects of adjunc-tive MMC are still to be evaluated.
MMC is an antimitotic antibioticwhich could, theoretically, adversely af-fect all cells with which significant con-centrations come into contact. After ap-plication, most surgeons copiously irri-gate the exposed tissues, but a certainamount of the drug does penetrate intothe adjacent tissues. Kawase et al. (1992)have determined that 0.4 mg/ml of MMCapplied beneath a lamellar scleral flap, tothe bed of a trabeculectomy, for 5 min-utes led to a trabecular block concen-tration of 5.4 to 1.2 mg/g in humans. Ex-perimental work has demonstrated the
toxicity of MMC to the corneal endo-thelium (Derick et al. 1991, McDermottet al. 1994). There are, however, no clin-ically controlled studies of the corneal en-dothelium following the intraoperativeuse of MMC.
We have prospectively studied the cor-neal endothelial cell count in patients un-dergoing trabeculectomy alone, with ad-junctive 0.2 mg/ml MMC and 0.4 mg/mlMMC. The control group allowed a com-parative evaluation of the effectivity andthe safety of this potentially toxic adju-vant.
Material and MethodsThirty eyes of consecutive adult patientsadmitted for a high risk glaucomasurgery were enrolled in the study afterclearance from our scientific protocolcommittee. Informed consent was ob-tained. All patients had a thorough pre-
operative examination including visualacuity, slit lamp evaluation, applanationtonometry, gonioscopy, fundus examin-ation and Goldmann perimetry. Centralcorneal endothelial counts were assessedby the contact technique using the AlconPRO corneal endothelial microscope pre-operatively and 3 months postoperativelyby a masked trained technician. Video re-cordings were taken randomly at threepoints on the central cornea, and withthe help of a grid a minimum of threecounts were done, averaged, and multi-plied by 50. Any previous surgery or laserprocedure was specifically noted.
The 30 eyes of these patients were ran-domly assigned to three groups, GroupI undergoing a standard trabeculectomy,Group II a trabeculectomy with intra-operative 0.2 mg/ml of MMC for 4 min-utes, and Group III a trabeculectomywith intraoperative 0.4 mg/ml of MMCfor 4 minutes. The mitomycin C wasmanufactured by Kyowa Company, Ja-pan, and was not cut with mannitol, butcontained sodium chloride. This was di-luted with sterile distilled water. The tra-beculectomy was performed by either oneof two glaucoma specialists, under a lim-bus based conjunctival flap and a halfthickness, 44 mm, lameller scleral flap.
A cellulose sponge surgical spear wascut when dry to a size of 44 mm andMMC of either concentration wasdropped on it till the sponge had ex-panded and the first drop fell out. Thiswas then placed beneath the scleral flapand covered with the conjunctiva, tak-ing care that the cut edge of the con-junctiva did not come into contact withthe sponge. After 4 minutes the spongewas removed and the area of appli-cation was thoroughly irrigated with aminimum of 10ml of Ringer lactatesolution. The area was swabbed dry andsubsequently the trabecular block was
A O S 1998
removed. The triangular trabeculectomyflap was closed with three sutures forapposition. No viscoelastic was used inany case. Postoperatively all eyes weretreated with antibiotic-steroid dropsfour times a day.
ResultsThirty eyes of 28 adult patients with highrisk glaucomas were randomly assignedto Group I, undergoing trabeculectomyalone, Group II, trabeculectomy with theintraoperative use of 0.2 mg/ml of mito-mycin C or Group III, trabeculectomywith intraoperative 0.4 mg/ml of mitomy-cin C.
The age of the patients ranged from2288 years; there were 17 males and 11females. The ocular diagnoses of the 30eyes were chronic angle closure glaucoma(6), aphakic glaucoma (5), uveitic glau-coma (5), concussional glaucoma (4), juv-enile glaucoma (4), open angle glaucoma(3), pseudophakic glaucoma (2) and Co-gan Reese syndrome (1).
There was no significant difference inthe preoperative intraocular pressure orendothelial count between the threegroups (Table 1). Postoperatively at 3months, the drop in the control Group Iwas only 7048.3 cells/mm2 as comparedto 26588.4 in Group II and 280122.9cells/mm2 in Group III. The percentagefall in the three groups was 3.732.73%,13.904.69%, and 14.527.80%, respec-tively. Statistical evaluation by the Twosample t test found a statistically sig-nificant difference, p0.001, betweenGroup I and II and a significant,
Table 1. Summary of Data(meanSD).
Group I Group II Group II(Controls) (0.2 mg/ml MMC) (0.4 mg/ml MMC)n10 eyes n10 eyes n10 eyes
Intra-ocular pressure (mmHg)Preoperative (on pilocarpine) 23.8 28.2 26.42% and Timolol 0.5% 2.62 6.2 4.48Postoperative 3 months 19 12 12.5(off medication) 4.81 2.11 3.31Endothelial Cell (Cell mm2)Preoperative 1985 1950 1995
242.7 479.6 330.4Postoperative (3 months) 1915 1685 1720
269.8 452.8 391Cell loss (3 months) 70 265 280
48.3 88.4 12.9Percentage cell loss 3.73 13.90 280(3 months) 2.73 88.4 122.9
p0.001 difference between Group I andIII. There was no significant differencebetween the two mitomycin groups,Group II and III. A non parametric test,Wilcoxens Signed Rank test, was alsodone with a statistically significant differ-ence noted, p0.01, between Group Iand II and Group I and III. Again therewas no statistically significant differencebetween Group II and III.
Six eyes had a significantly shallow an-terior chamber for between 2 and 4 weekspostoperatively with peripheral iridocor-neal touch, 1 in Group I, 2 in Group IIand 3 in Group III. Some eyes had ahigher endothelial cell loss than that seenin the rest of the respective groups, i.e.7.69% as compared to a mean of 2.96%in the rest of Group I, 19.43% of 12.52%in Group II and 24.99% of 10.03%. Threeeyes, two in the 0.2mg/ml MMC group(S.No. 16) and one in the 0.4 mg/mlMMC group (S.No. 9) had an unrec-ordably low tension with a formed,though shallow anterior chamber depthon the first postoperative day which re-turned to preoperative depth within thefirst week. S.No. 1 in the 0.2 mg/ml grouphad a drop in specular count of 14.58%,the other two lost 10% of their endo-thelial cells. An intraocular pressure ofless than 8 mmHg was seen in five others,S.No. 7 in the control group, S.Nos 2 and7 in the 0.2 mg/ml MMC group andS.Nos 3 and 6 in the 0.4 mg/ml group.There was a significantly higher cell lossin three of these, as compared to others intheir groups. No eye required a surgicalreformation of the anterior chamber.
Prior Nd YAG iridotomy (2 eyes), sur-gical iridectomy (1 eye), trabeculectomy
(5 eyes) and extracapsular cataract ex-traction (4 eyes) did not lead to a greaterendothelial cell loss after this surgery.However, one eye with previous intracap-sular lens extraction showed a cell loss of6.9% in Group I. Another eye that hadan iridencleisis and an intracapsular lensextraction had a loss of 28.57% in GroupIII. An earlier intracapsular lens extrac-tion with an anterior chamber intraocul-ar lens led to a cell loss of 20.0% in oneeye in Group II.
There was no significant difference inthe endothelial cell loss in patients belowand above and the age of 40 years, in anyof the three groups.
DiscussionMitomycin-C is being widely used intra-operatively for intractable and high riskglaucomas. Observations over the lasttwo years have brought to light the rela-tively short term complications of hypo-tony, extremely thin blebs and choroidaldetachment. The long term effects at thearea of application or in surroundingtissues are still being studied.
A chance observation led us to reviewthe literature on MMC and its effects onthe corneal endothelium. A patient withpseudophakic glaucoma developed local-ized corneal thickening and epithelialedema in relation to the area of appli-cation of the mitomycin-C, three monthsafter the surgery. This then led to a gener-alized bullous keratopathy over the nextnine months.
Derick et al. (1991) have shown that anintracameral injection of 50 ml of mito-mycin (0.5 mg/ml of balanced salt solu-tion) led to severe inflammation initially,followed by opacification and thickeningof the cornea within