|Year : 2019 | Volume
| Issue : 3 | Page : 67-77
Assessment of corneal endothelial cell changes caused by mitomycin-C application during pterygium surgery
Tarek M Radwan, Ahmed A Abdelghany, Amr A.F Ali, Ahmed A.B Abdel Aal
Ophthalmology Department, Faculty of Medicine, Suez Canal University, Ismailia City, Egypt
|Date of Submission||29-Mar-2019|
|Date of Acceptance||09-Jun-2019|
|Date of Web Publication||25-Sep-2019|
MD Ahmed A Abdelghany
Ophthalmology Department, Faculty of Medicine, Suez Canal University, Ismailia City, Postcode 41522
Source of Support: None, Conflict of Interest: None
Background Topical Mitomycin-C (MMC) can have a deleterious effect onto corneal endothelium in some ophthalmic surgeries.
Aim To evaluate safety of intraoperative topical MMC in pterygium surgeries onto corneal endothelium.
Design Prospective comparative cohort study.
Subjects and methods Forty-six patients were included in this study. Twenty-three patients underwent pterygium surgery with intraoperative MMC application (trial group) and equal number of patients underwent pterygium excision without MMC (control group) at the Suez Canal University Hospital. Corneal endothelial images were acquired with a specular microscope before surgery and at one week, one month, and three months following surgery.
Results Mean preoperative endothelial cell counts were 2364±220 cells/mm2 in the pterygium excision without MMC group and 2411±227 cells/mm2 in the pterygium excision with MMC group (P=0.7). One week, one month and three months after surgery, the pterygium with MMC group showed a statistically insignificant endothelial cell loss (P=0.06) whereas the other group didn’t encounter any decrease in ECD (P=0.349), similar insignificant changes were found between the different measurements in the follow-up periods as compared to the preoperative measurements of central corneal thickness (CCT), cellular hexagonality, coefficient of variation and standard deviation of cell area as well as between patients of both groups.
Conclusions A single intraoperative 0.02% MMC topical application using MMC solution-moistened cellulose sponges, onto the scleral bed under the conjunctiva with care not to touch the cornea has not resulted in a statistically-significant deleterious effect onto corneal endothelium.
Keywords: endothelial cell loss, pterygium recurrence, specular microscopy
|How to cite this article:|
Radwan TM, Abdelghany AA, Ali AA, Abdel Aal AA. Assessment of corneal endothelial cell changes caused by mitomycin-C application during pterygium surgery. J Egypt Ophthalmol Soc 2019;112:67-77
|How to cite this URL:|
Radwan TM, Abdelghany AA, Ali AA, Abdel Aal AA. Assessment of corneal endothelial cell changes caused by mitomycin-C application during pterygium surgery. J Egypt Ophthalmol Soc [serial online] 2019 [cited 2020 Feb 21];112:67-77. Available from: http://www.jeos.eg.net/text.asp?2019/112/3/67/267820
| Introduction|| |
Pterygium carries a significant burden among ocular disorders, with a prevalence varying from 1% up to 15% depending on geographical location of population in relation to equatorial region  reaching up to 33% in some populations . Long periods of exposure to ultraviolet rays including those originating from the sun, as well as exposure to dust have been implicated in its occurrence , and also genetics seems to play a role in pterygium growth .
Whether removed for visual or cosmetic purposes or for recurrent inflammation or globe restriction ,, the most important sequelae that may occur after pterygium excision is a high recurrence rate, which − after simple excision without adjuvant treatment − ranges from 24 to 89% .
Intraoperative or postoperative topical application of mitomycin-C can reduce recurrence rates down to 10% ,,, owing to it potent antiproliferative and cytotoxic effects on fibroblasts , but deleterious effect of mitomycin-C on corneal endothelium has been demonstrated following augmented trabeculectomy interventions , and photorefractive keratectomy procedures ,.
Corneal endothelium plays a central role in maintenance of corneal transparency through maintaining its relative state of dehydration or corneal deturgescence ,,.
This research is therefore conducted not only to assess possible deleterious effects of topical application of mitomycin-C during pterygium excision surgery but also to quantify this possible effect to test and re-assess different and sometimes contradicting results previously published in literature about the same issue, and subsequently aiming at testing safety of this method of prevention of pterygium recurrence.
| Patients and methods|| |
This prospective comparative cohort study was granted the prerequisite acceptance from the Medical Bioethics Committee at Faculty of Medicine, Suez Canal University, in which 46 patients were recruited from the Ophthalmology Outpatient Clinic in Suez Canal University hospital in Ismailia City, Egypt.
The study included patients of either sex aged between 20 and 70 years old, who had a primary pterygium encroaching onto more than 3 mm of cornea from the limbus , through which episcleral vessels were still visible (atrophic to intermediate primary pterygium according to Tan’s classification) .
All patients who had corneal endothelial dystrophy, ongoing ocular pathology negatively affecting corneal endothelial count such as glaucoma, uveitis, keratitis, connective tissue disorders, diabetes mellitus have been excluded from the study; additionally, pseudophakic patients, contact lens wearers, patients with prior ocular chemical injury, patients who underwent keratoplasty, or patients with prior intravitreal injection have also been excluded.
The patients were randomly and equally assorted into two groups: group A was the trial group in which intraoperative mitomycin-C application was integrated as a part of the pterygium excision surgery, whereas group B was the control arm in which the participants underwent standard pterygium excision surgery without adjunctive intervention.
Complete medical history with emphasis on past history regarding ocular pathologies, surgeries, chemical injuries, contact lens wearing, the distant visual acuity measurement using Landolt C chart, subjective refraction, applanation tonometry, and slit-lamp examination were carried out for all patients. Binocular indirect ophthalmoscopic fundus examination was also done for all patients.
Baseline preoperative corneal endothelial cell count expressed as endothelial cell density (ECD), SD of cell area, coefficient of variation (CV, an objective index for polymegathism), percentage of cellular hexagonality (Hex%, an index for pleomorphism) as well as central corneal thickness (CCT) were all measured at the corneal central and autoanalyzed using automated noncontact specular microscope NIDEK CEM-530 device with integrated optical pachymetry, software version SOFT v1.10.02 (Nidek, Hiroishi, Japan).
This model of noncontact automated specular microscope is capable of studying the corneal endothelium and measuring the corneal thickness, with a capture field of 0.25 mm (W)×0.55 mm (H) providing a wide-field highly magnified image. It can examine one central point and eight paracentral points with 45° spacing, each of which locates at ∼5° angular distance from central point as seen by the examined person. It can also examine six peripheral points with 60° spacing, each of which locates at ∼27° angular distance from central point as seen by the examined person. Multiple photos can be captured and analyzed within seconds. Automated analysis includes different parameters of endothelial structure and two detailed graphic and color-coded analyses including apex graph for plotting polymegathism and apex graph for plotting pleomorphism. Standardized surgical technique for pterygium excision was implemented as follows: conjunctival anesthesia induction using benoxinate hydrochloride drops (Benox; Epicio Inc., 10th Ramadan, Alsharkia, Egypt) augmented with subconjunctival injection of 0.5 ml volume of 2% lidocaine (Debocaine; Al-Debeiky, Cairo, Egypt) and 1/200 000 adrenaline (Epinephrine; Misr Co., Alqaliubiya, Egypt) mixture into body of the pterygium using a 28-G hypodermal needle was carried out followed by avulsion of pterygium head and cap from the cornea and then dissection of pterygium body using a #15 surgical blade with the adjacent Tenon capsule was done followed by excision using Westcott scissors, resulting in the exposure of bare sclera.
In group A patients, mitomycin-C solution was prepared at concentration of 0.02% (0.2 mg/ml) by adding 10 ml of water for injection (Otsuka-Ateco, Cairo, Egypt) to a mitomycin 10 mg vial (Mitomycin-C; Biochem GmbH, Karlsruhe, Germany) containing 10 mg of mitomycin-C powder, and then diluting 0.1 ml of the resultant solution with 0.4-ml water for injection.
After moistening surgical cellulose sponge (Alcon, Fort Worth, Texas, USA) with 3–4 drops of the solution, it was directly applied to bare sclera for 3 min, exposing the undersurface of conjunctiva to it. Meticulous care was taken to avoid touching peripheral cornea with the mitomycin-C-moistened sponge. At the end of the 3 min, removal of the microsponge was followed by thorough ocular surface washing using balanced salt solution (∼200 ml of ringer’s lactate; Otsuka-Ateco). Surgery was accomplished leaving a small bare scleral area.
In group B, patients underwent pterygium excision with bare sclera technique, and no adjunctive usage of mitomycin-C was done (control group).
All patients received similar postoperative topical medications including daily five doses of tobramycin 0.3%/dexamethasone 0.1% eye drops (Tobradex eye drops; Alcon), a similar ointment form at bed time, and lubricant eye gel containing carbomer and vitamin A (Cornetears; Orchidia, Egypt), with gradual tapering of the treatment after the first-week by decreasing one eye drop topical application every week over next 4 weeks. Ibuprofen 400 mg tablets (Brufen; Abbott Laboratories, Chicago, Illinois, USA) thrice daily for 1 week were also prescribed as an analgesic.
All patients were examined on the first day, the first-week, the first-month, and the third-month postoperatively. On each follow-up visit, full ophthalmological examination was done, including slit-lamp examination of the anterior segment to assess postoperative wound healing of cornea and conjunctiva, possibility of pterygium recurrence, and exclude anterior segment possible complications such as inflammation and rise of intraocular pressure (IOP), and specular microscope was used to assess the central corneal endothelial changes on the first-week, first-month, and third-month follow-up visits. Recurrence was defined as any fibrovascular proliferation invading more than 1.5 mm of the cornea .
Specular microscopy (NIDEK CEM-530; Nidek, Hiroishi, Japan) with integrated optical pachymetry was used preoperatively, as well as on the first-week, first-month and third-month postoperative follow-up visits to take three measurements of each variant, that is, ECD, SD, CV, Hex, and CCT, and the average of each variant’s three measurements was calculated to ensure consistency of results ,. Any of the three measurements must be derived from an image containing at least 75 countable cells .
The main outcome measures were any possible change of endothelial cell count from the baseline preoperative value as well as associated changes in SD of cell area, CV, Hex, and CCT.
Data were fed to the computer and analyzed using IBM SPSS software package version 24.0 (IBM Corp., Armonk, New York, USA). The Kolmogorov–Smirnov test was used to verify the normality of distribution. Quantitative data were described using range (minimum and maximum), mean, SD, and median. Significance of the obtained results was judged at the 5% level where P value was less than 0.05. The used tests were Student t-test for normally distributed quantitative variables, to compare between two studied groups to assess the effect of pterygium excision surgery per se onto thee corneal endothelium, and analysis of variance with repeated measures for normally distributed quantitative variables, to compare between the different follow-up points of assessment.
Every participant was informed about the aim of the study and its benefit to him and to the community. Written consents were obtained from participants before enrolling them in the study, and they had the right to refuse participation without any effect on their management. Proper medical treatment protocols were applied to all participants. All data obtained from participants were used for scientific purposes only. No harmful maneuver was performed nor used. Researcher phone number and all possible communicating methods were explained to the participants to contact the researcher at any time for any inquiry. All participants were announced of results of the study. All participants had the right to withdraw from the study at any time without giving any reason.
| Results|| |
A total of 46 patients were enrolled in the study and equally divided into two groups: group A included patients who underwent pterygium excision surgery with intraoperative mitomycin-C application, and group B included patients who underwent pterygium excision surgery without mitomycin-C application. Only the results of 20 patients per group were analyzed after some participants have been excluded.
Three patients in group A have been excluded: one dropped follow-up visits, another developed accelerated form of mature cataract for which uneventful phacoemulsification procedure was arranged to avoid developing intumescent cataract, and the third patient was excluded owing to elevated IOP during the first-month postoperative period as a steroid response and was effectively brought under control by steroid tapering and temporarily twice-daily antiglaucoma eye drops (brimonidine tartrate 0.2%/timolol maleate 0.5%).
Similarly, in group B, three patients have been excluded: two of them rapidly developed aggressive form of recurrent pterygium that was managed by pterygium excision surgery with combined intraoperative mitomycin-C 0.02% application together with conjunctival rotational flap, and the third one developed steroid response rise in IOP that was effectively controlled by steroid tapering and temporarily twice-daily antiglaucoma eye drops (brimonidine tartrate 0.2%/timolol maleate 0.5%).
Mean age in group A was 51.50±7.98 years, whereas in group B was 52.1±8.35 years, with no statistically significant difference (P=0.7602).
Percentage of males in group A was 50% whereas in group B was 45.45% with no significant effect of sex on results (P=0.7627).
Overall, 45% of group A patients had pterygium in their right eye, whereas in group B, the percentage reached 59%, with no statistically significant difference (P=0.3652) ([Table 1]).
|Table 1 Age, sex, and side of the operated eye in each of the two study groups|
Click here to view
In group A, where mitomycin-C was used intraoperatively, mean preoperative ECD was 2411±227 cells/mm2, 1-week postoperatively mean ECD was 2385±208 cells/mm2, at 1-month follow-up was 2388±222 cells/mm2, and the third-month follow-up mean ECD was 2403±220 cells/mm2, and all these changes were of no statistical significance (P=0.06) ([Figure 1]).
|Figure 1 Mean postoperative endothelial cell density values in each assessment measurement compared with preoperative values in each group.|
Click here to view
Corneal endothelium morphological parameters did not show significant change postoperatively as compared with their preoperative values. The mean preoperative SD of cell area was 113±20 μm2, whereas postoperative values were 115±18, 114±17, and 114±17 μm2 at 1 week, 1 month and 3 months, respectively (P=0.841). Mean preoperative CV was 28±4% whereas postoperatively it was 29±4, 29±3, and 29±3% at 1 week, 1 month, and 3 months, respectively (P=0.788) ([Figure 2]). Postoperative 1-week mean Hex (69±3%), 1 month mean Hex (70±2%), and 3-month mean Hex (70±2%) did not differ significantly from preoperative mean Hex (70±3%) (P=0.27) ([Figure 3]), and CCT followed the same pattern of insignificant changes postoperatively (1-week measurement was 537±41 μm, 1-month value was 534±42 μm, and 3-month postoperative CCT was 537±41 μm) as compared with preoperative mean CCT (537±41 μm) (P=0.073) ([Table 2]).
|Figure 2 Mean postoperative values of coefficient of variation in cell area from each follow-up measurement compared with preoperative measurements in each group.|
Click here to view
|Figure 3 Mean postoperative percentage of cell hexagonality at each follow-up assessment compared with preoperative measurements in each group.|
Click here to view
|Table 2 Comparison between the group A different follow-up measurements with their baseline preoperative values regarding endothelial cell density, coefficient of variation, and hexagonality|
Click here to view
In group B patients who underwent pterygium excision surgery without intraoperative Mitomycin-C (MMC) application, the mean preoperative ECD was 2364±220 cells/mm2 and postoperative values were 2375±214, 2375±230, and 2440±374 cells/mm2 at 1 week, 1 month, and 3 months, respectively (P=0.35) ([Figure 1]). Mean preoperative CV was 29.47±4.20%, whereas 1-week postoperative measurement was 28.94±3.90%, 1-month mean CV was 29.02±4.03%, and 3-month mean CV was 29.53±3.93% ([Figure 2]). All these changes were still of no statistical significance (P=0.201). Preoperative mean±SD of cell area was 118±21 μm2, whereas the mean postoperative values were 117±21, 118±21, and 117±20 μm2 at 1 week, 1 month, and 3 months, respectively, without any statistically significant difference (P=0.829).
Percentage of hexagonal cells did not encounter significant change in the control group patients as compared with their preoperative mean value ([Figure 3]), with preoperative mean Hex of 69.14±3.66%, whereas postoperative 1-week measurement was 68.55±4.05%, 1-month measurement was 68.61±3.51%, and 3-month postoperative value was 68.83±3.82% (P=0.675). Similarly mean postoperative CCT at 1-week follow-up assessment was 524±28 μm, at 1 month was 524±29 μm, at 3 months was 525±29 μm, and all these values did not show significant changes compared with the baseline mean preoperative value of 523±30 μm ([Table 3]).
|Table 3 Comparison between the group B different follow-up measurements with their baseline preoperative values regarding endothelial cell density, coefficient of variation, and hexagonality|
Click here to view
Almost all patients of both groups had ocular surface symptoms including gritty sensation, burning, and red eye. Four patients in group A (17.4%) and five in group B (21.7%) had subconjunctival hemorrhage. Only one patient in MMC group (∼4.3%) had corneal symptoms such as photophobia, lacrimation, and blepharospasm owing to epithelial defect, which healed without additional measures, leaving no sequelae on the seventh day postoperative, and another patient in the same group (∼4.3%) developed accelerated form of mature white cataract; the patient was excluded from the study and underwent uneventful phacoemulsification surgery.
One patient in each group developed steroid response rise in IOP, which was managed by rapid tapering of topical steroid over only 1 week with temporary antiglaucoma eye drops (brimonidine tartrate 0.2%/timolol maleate 0.5% twice-daily for 2 weeks). No serious complications were noticed in the study period. Two recurrent cases were diagnosed in group B (∼8.7%) during the study period and were excluded for further combined MMC and conjunctival rotational flap. No recurrent cases were documented during the study period among group A patients ([Table 4]).
|Table 4 Comparison between the two groups different follow-up measurements with each other regarding endothelial cell density, coefficient of variation, and hexagonality|
Click here to view
| Discussion|| |
This prospective comparative cohort study was aimed at assessment of corneal endothelial changes that may occur as a result of topical intraoperative application of mitomycin-C during pterygium excision surgery among patients attending the Ophthalmology Clinic at Suez Canal University Hospital, by comparing the preoperative and early postoperative changes with their control group that underwent the same operation without mitomycin-C application.
Bahar et al.  have shown that pterygium excision surgery without intraoperative mitomycin-C was not associated with significant changes in the endothelial cell parameters postoperatively as compared with preoperative baseline measurements. The mean preoperative endothelial cell density of 2330±318 cells/mm2, and postoperative mean ECD values were 2401±269 (P=0.08), 2350±249 (P=0.88), and 2456±314 cells/mm2 (P=0.51) at 1 week, 2 month, and 3 months, respectively. Mean preoperative CV was 35.3±7%, whereas postoperatively the mean CV was 36.1±6.8% at 1 week (P=0.62), 35.7±9.9% at 2 month (P=0.49), and at 35.3±6.7% 3 months (P=0.25). Similar insignificant changes in cell Hex were described, with the mean preoperative percentage of hexagonal cells was 53.8±12.7%, whereas postoperative values were 56.6±11.2% at 1 week (P=0.47), 55.9±12.4% at 1 month (P=0.50), and 55.2±10.5% at 3 months (P=0.96). Mean preoperative CCT was 561±34 μm, and postoperatively, at 1 week, the mean CCT was 554±33 μm, which decreased in 1-month follow-up assessment to 543±31 μm to increase again to 553±33 μm at 3 months (P=0.29).
These results agreed with our study’s control group patients who underwent pterygium excision surgery without intraoperative MMC application, with no statistically significant changes demonstrated either in any endothelial parameters or in corneal pachymetry. Therefore, pterygium excision surgery per se has no significant effect on either the corneal endothelial parameters or its pachymetry.
Contradictory results were found in the literature about intraoperative topical MMC during pterygium excision surgeries. Avisar et al.  concluded that topical intraoperative mitomycin-C 0.02% for 5 min after excision of the primary pterygium could result in immediate and substantial loss of endothelial cell density of about 21.25, 24.26, and 21.05% at 1 week, 1 month, and 3 months postoperative follow-up assessments, respectively, whereas Bahar et al.  described only a modest decrease in ECD at the 1-month postoperative follow-up assessment of only 6% (P=0.003), which was reduced at 3-month follow-up assessment to only 4% loss of ECD (P=0.05), but in that study, MMC was used only in the patients who had recurrent pterygium, and for duration of only 2 min. The authors described a statistically significant decrease in mean Hex from preoperative value of 63.2±15.3–53.4±9.8% at 1 month postoperatively (P=0.02), with a corresponding increase of CV from mean preoperative value of 28.9±10.1–35.5±6.8% at 1-month postoperative assessment (P=0.007) and 35±7.7% at 3 months postoperatively (P=0.04). They also described a decrease in CCT that occurred 1 month postoperatively with mean CCT 550±49 μm as compared with mean preoperative CCT of ∼562±44 μm. Similar decrease was found at 3 months postoperatively, with a value of ∼548±44 μm, and despite being of statistical significance, this decrease in CCT lacks any clinical significance.
Pérez-Rico et al.  observed that 1-min intraoperative application of 0.02% MMC had no adverse effect on ECD, CV, CCT, and Hex. In their study, all measurements were performed preoperatively and at 10 days, 1 month, and 3 months postoperatively. The respective mean ECDs at those follow-up visits were 2382±342, 2371±337, 2383± 333, and 2385±357 cells/mm2 (P=0.96). The respective mean CVs were 34.31±5.62, 35.08±6.67, 35.39±7.39, and 35.29±7.50% (P=0.17). The respective mean Hex % values were 52.98±7.32, 52.25±8.85, 51.92±8.29, and 51.61±8.98% (P=0.48). The respective mean pachymetry measurements were 506.65±36.87, 502.31±38.72, 498.55±43.15, and 502.08±41.33 μm. The differences were not significant (P=0.99).
The main differential aspect in the previous studies was the duration of application of MMC, with Avisar et al.  applying MMC for 5 min, hence the highest deleterious effect seen among the similar studies, peaking up to 24.26% loss of ECD at 1 month postoperatively, whereas Bahar et al.  shortened the duration of MMC application to only 2 min, hence the highest loss of ECD described by them was only 6% at 1 month postoperatively, and the study by Pérez-Rico et al.  study made the duration of MMC application only 1 min, with a resultant insignificant change of ECD; all the three studies used the same concentration of 0.02% MMC (0.2 mg/ml).
The effect of duration of topical intraoperative application of MMC on its deleterious effects onto cornea was studied by Kheirkhah et al.  and concluded that the location of application of MMC whether directly onto the bare sclera or under the remnant conjunctival bed will not alter the effect of MMC onto corneal endothelium, but the duration of application of MMC resulted in a significant difference in ECD loss within the same group. The postoperative 1-week percentage of ECD loss in the scleral group was 5.2±2.1, 9.7±1.5, and 14.6±4% among patients who underwent topical MMC application for 1, 3, and 5 min, respectively.
After 1 month postoperatively, these changes become less evident but still with higher ECD loss in patients with prolonged intraoperative MMC. Very similar values were found in the subconjunctival group, with no statistically significant difference between both groups.
On the contrary, a 10-year study conducted by Young et al. , perhaps the longest controlled study in the literature that addressed MMC effect onto corneal endothelium in pterygium surgery patients, revealed no statistically significant long-term loss of ECD, which may be attributed to intraoperative 0.02% MMC for 5 min during pterygium excision surgery. This study compared the intraoperative MMC application versus limbal conjunctival autograft (LCAU) in terms of pterygium recurrence rates as well as harmful effect onto corneal endothelium. In the MMC arm, the mean ECD at the end of the study in the eye with pterygium excision surgery and intraoperative MMC was 2392±342 cells/mm2 whereas in the sound eye used as a control, mean ECD was 2406±365 cells/mm2, with no statistically significant difference between both eyes and even between MMC and LCAU groups (mean ECD in LCAU group was 2390±388, P=0.468).
Our study results agreed with the findings of Young et al. , the mean ECD in group A patients who underwent pterygium excision surgery with intraoperative 0.02% MMC for 3 min showed a statistically insignificant decrease of ∼26 cells/mm2 in the first-week postoperative follow-up measurement in comparison with the preoperative value, which later on recovered to only loss of 23 cells/mm2 in the first-month follow-up, and then on the third-month visit, this loss was only ∼8 cells/mm2.
These little changes, despite lacking statistical significance, may point towards either an actual decrease in ECD which has recovered later on as suggested by Bahar et al.  as well as Kheirkhah et al. , or simply this decrease is mostly artifactual in origin owing to the reproducibility issue of specular microscope, which may result in variability in ECD count within ±2–4%  up to 7%  and this could be seen in the other control arm of the study, where the ECD values even increased in the postoperative follow-up visits to reach 2375 and 2440 cells/mm2in the first-month and third-month follow-up visits in comparison with preoperative value of ∼2364 cells/mm2.
Other corneal endothelium morphological parameters did not show significant change postoperatively as compared with their preoperative values.
The discrepancy between results from all the aforementioned studies originates from several confounding sources. Avisar et al.  used sharp dissection to remove the pterygium head and neck from corneal surface using #15 surgical blade to do limited keratectomy, with a resultant removal of some stromal bed, increasing permeability of MMC into thinned cornea. They applied MMC for a relatively long duration of 5 min before doing thorough wash with balanced salt solution, and hence the higher possibility of more MMC to gain access to corneal endothelium. They also soaked the surgical sponge with MMC solution, increasing the possibility of the excess MMC solution to be squeezed from the sponge upon its application onto bare sclera and again reaches the epithelium-denuded cornea, damaging its endothelium. All these factors may have contributed in the very high negative effect on ECD loss up to 24.26% at 1-month follow-up assessment.
Bahar et al.  reduced duration of application of intraoperative 0.02% MMC to only 2 min with a resultant ECD loss of ∼6% 1 month postoperatively that stabilized at only 4% at 3 months postoperatively, but the main difference in this study was the type of pterygium among patients who underwent pterygium excision surgery with intraoperative MMC application. Those patients all had recurrent pterygium. In addition to the already thinned cornea, these patients usually undergo aggressive keratectomy to address the pterygium recurrence onto the corneal proper, with a more and more corneal thinning that facilitates access of MMC toward corneal endothelium. Again, these authors used the soaking method in preparing the surgical sponges with MMC solution, hazarding to expose the cornea to the squeezed excess MMC solution.
Pérez-Rico et al.  markedly shortened the duration of scleral exposure to MMC to only 1 min and paid meticulous care not to touch the peripheral cornea to the surgical microsponge, hence showed insignificant changes in the corneal endothelium.
In this study, avulsion method was done to remove the pterygium head and cap from the cornea, hence avoiding excessive keratectomy, which may result in excessive thinning of cornea. We only moistened (no soaking) the surgical sponges with MMC so as to avoid excess 0.02% MMC solution getting squeezed out of the cellulose sponge onto adjacent cornea. Great care was exerted not to touch the cornea with the moistened microsponge. Tight adherence to the 3 min duration of MMC application onto the scleral bed under the conjunctival surface was done, followed by thorough wash using balanced salt solution. All these measures were thought not only to decrease possibility of MMC reaching corneal endothelium, but also decrease its other possible complications, such as aseptic scleritis and scleral necrosis, corneal melting, secondary glaucoma, persistent epithelial defect, and cataract ,,. In fact, most of these serious complications have been described in the literature with postoperative topical MMC usage as eye drops ,,.
An interesting finding reported by Frucht-Pery et al.  is the localized effect of topical intraoperative MMC. They conducted a study to evaluate the efficacy of 0.02% MMC intraoperative application versus sham treatment (normal saline 0.9%) in prevention of pterygium recurrence. Two patients of the MMC group had nasal and temporal pterygia, for which only the scleral bed of the nasal excised pterygium received intraoperative 0.02% MMC for 5 min, whereas the other temporal side did not receive any adjunctive treatment. Interestingly, the pterygium recurred in the temporal side of both patients, whereas the nasal side remained free of recurrence. Such pattern of very localized effect of single intraoperative MMC application has been proven even in animal studies , and this may reinforce our study results, as well as the results of Young et al. , in that both studies neither demonstrated a harmful effect onto corneal endothelium nor demonstrated sight=threatening complications such as necrotizing scleritis or corneal melting owing to meticulous care about precisely limiting the area of MMC exposure.
One patient in group A who underwent intraoperative MMC application had an accelerated form of mature white cataract. The patient was a 57-year-old woman. Her eye with the pterygium had a visually insignificant cataract and her best corrected distant visual acuity (BCDVA) was 6/9 in this eye. She reported gradual painless progressing diminution of vision postoperatively, and on the day 34 postoperatively, she had a full-blown picture of mature white cataract, but IOP was 16 mmHg. She was excluded from the study and underwent uneventful phacoemulsification surgery. It is not clear in this patient why this accelerated cataractogenesis occurred. Diabetes was excluded by laboratory results. Topical steroid may have had a role. However, Rubinfeld et al.  reported two similar cases in a case-series study. The authors used the phrase ‘sudden-onset mature cataract’ to describe this accelerated cataract maturation in their paper’s abstract. They also described other serious complications up to corneal perforation, iritis, and secondary glaucoma, but the main difference between that study and ours is that they prescribed the MMC in the form of postoperative topical eye drops, with the hazard of excessive self-treatment, drug accumulation, and the unnecessary exposure of the whole anterior segment to the effect of this potent cytotoxic drug. Indeed, this has been found in many other studies ,.
Another important factor in measuring any parameter of a biological tissue is the reproducibility of measurements. Pop et al.  reported a variation in ECD on repeated measurements up to 4.1%, whereas Bourne et al.  reported this variation in ECD repeatability of measurements up to 7%, but all the aforementioned studies − including our study − minimized this effect by taking the average of three measurements of each parameter in each follow-up assessment.
Our study had some limitations that may establish a base for future research. The sample size after exclusion of some patients is relatively small (20 patients/group) but still within the preset dropout limit. Another limitation is the relatively short period of postoperative follow-up, and also our study design lacks blinding, which is useful to minimize biases.
| Conclusion|| |
Single intraoperative 0.02% MMC topical application using MMC solution-moistened microsponge onto the scleral bed under the conjunctiva with care not to touch the cornea has not resulted in a statistically significant deleterious effect onto corneal endothelium.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Saw SM, Tan D. Pterygium: prevalence, demography and risk factors. Ophthalmic Epidemiol 1999; 6:219–228.
Droutsas K, Sekundo W. Epidemiologie des pterygiums. Ophthalmologe 2010; 107:511–516.
Coroneo MT. Pterygium as an early indicator of ultraviolet insolation: a hypothesis. Br J Ophthalmol 1993; 77:734–739.
Anguria P, Kitinya J, Ntuli S, Carmichael T. The role of heredity in pterygium development. Int J Ophthalmol 2014; 7:563–573.
Alpay A, Uğurbaş SH, Erdoğan B. Comparing techniques for pterygium surgery. Clin Ophthalmol 2009; 3:69.
Hirst LW. The treatment of pterygium. Surv Ophthalmol 2003; 48:145–180.
Jaros Patricia A, Deluise VP. Pingueculae and pterygia. Surv Ophthalmol 1988; 33:41–49.
Rahman A, Yahya K, Hasan KU. Recurrence rate of pterygium following surgical excision with intraoperative versus postoperative mitomycin-C. J Coll Physicians Surg Pak 2008; 18:489–492.
Lam DS, Wong AK, Fan DS, Chew S, Kwok PS, Tso MO. Intraoperative mitomycin C to prevent recurrence of pterygium after excision: a 30-month follow-up study. Ophthalmology 1998; 105:901–905.
Manning CA, Kloess PM, Diaz MD, Yee RW. Intraoperative mitomycin C in primary pterygium excision.A controlled randomized trail. Ophthalmology 1997; 104:844–848.
Mutlu FM, Sobaci G, Tatar T, Yildirim E. A comparative study of recurrent pterygium surgery: limbal conjunctival autograft transplantation versus mitomycin C with conjunctival flap. Ophthalmology 1999; 106:817–821.
Mudhol RR, Zingade ND, Mudhol RS, Harugop AS, Das AT. Mitomycin C in ophthalmology. J Sci Soc 2012; 39:4. [Full text]
Storr-Paulsen T, Norregaard JC, Ahmed S, Storr-Paulsen A. Corneal endothelial cell loss after mitomycin C-augmented trabeculectomy. J Glaucoma 2008; 17:654–657.
Mietz H, Roters S, Krieglstein GK. Bullous keratopathy as a complication of trabeculectomy with mitomycin C. Graefes Arch Clin Exp Ophthalmol 2005; 243:1284–1287.
Morales AJ, Zadok D, Mora-Retana R, Martínez-Gama E, Robledo NE, Chayet AS. Intraoperative mitomycin and corneal endothelium after photorefractive keratectomy. Am J Ophthalmol 2006; 142:400–404.
Nassiri N, Farahangiz S, Rahnavardi M, Rahmani L, Nader N. Corneal endothelial cell injury induced by mitomycin-C in photorefractive keratectomy: nonrandomized controlled trial. J Cataract Refract Surg 2008; 34:902–908.
Yee RW, Geroski DH, Matsuda M, Champeau EJ, Meyer LA, Edelhauser HF. Pump function of the human corneal endothelium. Ophthalmology 1985; 92:759–763.
Maurice DM. The location of the fluid pump in the cornea. J Physiol 1972; 221:43–54.
Hodson S. Evidence for a bicarbonate-dependent sodium pump in corneal endothelium. Exp Eye Res 1971; 11:20.
Galin MA, Lin LL, Fetherolf E, Obstbaum SA, Sugar A. Time analysis of corneal endothelial cell density after cataract extraction. Am J Ophthalmol 1979; 88:93–96.
Tan DT, Chee SP, Dear KB, Lim AS. Effect of pterygium morphology on pterygium recurrence in a controlled trial comparing conjunctival autografting with bare sclera excision. Arch Ophthalmol 1997; 115:1235–1240.
Prabhasawat P, Barton K, Burkett G, Tseng SC. Comparison of conjunctival autografts, amniotic membrane grafts, and primary closure for pterygium excision. Ophthalmology 1997; 104:974–985.
Bourne WM, Nelson LR, Hodge DO. Central corneal endothelial cell changes over a ten-year period. Invest Ophthalmol Vis Sci 1997; 38:779–782.
Pop M, Payette Y. Initial results of endothelial cell counts after Artisan lens for phakic eyes: an evaluation of the United States Food and Drug Administration Ophtec Study. Ophthalmology 2004; 111:309–317.
Doughty MJ, Müller A, Zaman ML. Assessment of the reliability of human corneal endothelial cell-density estimates using a noncontact specular microscope. Cornea 2000; 19:148–158.
Bahar I, Kaiserman I, Lange AP, Slomovic A, Levinger E, Sansanayudh W, Slomovic AR. The effect of mitomycin C on corneal endothelium in pterygium surgery. Am J Ophthalmol 2009; 147:447–452.e1.
Avisar R, Avisar I, Bahar I, Weinberger D. Effect of mitomycin C in pterygium surgery on corneal endothelium. Cornea 2008; 27:559–561.
Pérez-Rico C, Benítez-Herreros J, Montes-Mollón MÁ, Germain F, Castro-Rebollo M, Gómez-SanGil Y et al.
Intraoperative mitomycin C and corneal endothelium after pterygium surgery. Cornea 2009; 28:1135–1138.
Kheirkhah A, Izadi A, Kiarudi MY, Nazari R, Hashemian H, Behrouz MJ. Effects of mitomycin C on corneal endothelial cell counts in pterygium surgery: role of application location. Am J Ophthalmol 2011; 151:488–493.
Young AL, Ho M, Jhanji V, Cheng L. Ten-year results of a randomized controlled trial comparing 0.02% mitomycin C and limbal conjunctival autograft in pterygium surgery. Ophthalmology 2013; 120:2390–2395.
Dunn JP, Seamone CD, Ostler HB, Nickel BL. Development of scleral ulceration and calcification after pterygium excision and mitomycin therapy. Am J Ophthalmol 1991; 112:343–344.
Dougherty PJ, Hardten DR, Lindstrom RL. Corneoscleral melt after pterygium surgery using a single intraoperative application of mitomycin-C. Cornea 1996; 15:537–540.
Rubinfeld RS, Pfister RR, Stein RM, Foster CS, Martin NF, Stoleru S et al.
Serious complications of topical mitomycin-C after pterygium surgery. Ophthalmology 1992; 99:1647–1654.
Ewing-Chow DA, Romanchuk KG, Gilmour GR, Underhill JH, Climenhaga DB. Corneal melting after pterygium removal followed by topical mitomycin C therapy. Can J Ophthalmol 1992; 27:197–199.
Gupta S, Basti S. Corneoscleral, ciliary body, and vitreoretinal toxicity after excessive instillation of mitomycin C (letter). Am J Ophthalmol 1992; 114:503–504.
Frucht-Pery J, Siganos CS, Ilsar M. Intraoperative application of topical mitomycin C for pterygium surgery. Ophthalmology 1996; 103:674–677.
Khaw PT, Doyle JW, Sherwood MB, Grierson I, Schultz G, McGorray S. Prolonged localized tissue effects from 5-minute exposures to fluorouracil and mitomycin C. Arch Ophthalmol 1993; 111:263–267.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]