Mucous Membrane Grafting Augmented with Topical Mitomycin C Application in Contracted Socket Repair Surgeries

Introduction

Contracted socket is the condition in which there is a decrease in the depth of fornices and the orbital volume because of shrinkage of orbital tissue so that an ocular prosthesis could not be retained in place properly. This will lead to severely impaired function and bad cosmetic result that would be negatively reflected on the psychological state of those patients. Many techniques have been developed to reconstruct the fornices in an attempt to maintain prosthesis in place with the least possible cosmetic complications. However, recurrence is still very common.^1,2

Recurrent socket contraction is the result of contracture of surgical bed that requires repeated surgery. In contrast, multiple surgeries can further accentuate scarring and render the case inoperable. Therefore, prevention of postoperative scarring in the surgical bed of the socket is an essential key to success. ³

The use of antifibrotic agents in pterygium surgery to prevent recurrence and in glaucoma surgery to prevent postoperative fibrosis has become common practice.^4–6 Most commonly used antifibrotic agents in ophthalmic surgeries are mitomycin C (MMC) and 5-Fluorouracil (5-FU). MMC acts as an alkylating agent and potent fibroblast inhibitor, which can cause irreversible damage to the cell. Besides, it also inhibits migration of fibroblast and synthesis of collagen and, therefore, affects wound healing. ⁷ 5-FU, in contrast, is an antimetabolite agent that hinders progression of fibrosis in the course of wound healing and was used in recurrent socket contraction cases. ⁸

The purpose of this study is to evaluate the use of intraoperative topical application of MMC for managing cases of recurrent socket contraction.

Methods

This is a prospective comparative randomized study. It was carried out at the Ophthalmology Department, Menoufia University Hospitals, Egypt, in the period from March 2013 till March 2016. The study included 40 patients suffering from contracted sockets. They were randomly enrolled into 2 groups. Group A included 20 patients who had a surgery to treat contracted socket without augmentation with MMC. Group B patients had an MMC-augmented repair for the contracted socket. After obtaining the necessary approval from Faculty Ethics Committee, a detailed discussion about the risk and benefits of the operation was carried out with all patients and a written consent was obtained. All measures were in accordance with the tenets of the Declaration of Helsinki.

Patients included in the study were older than 18 years with only shallow inferior fornix (IF). All patients had a history of only 1 surgery for repair of a contracted socket with subsequent recurrence at least 6 months before inclusion in the study. We excluded patients younger than 18 years old, patients with congenital anophthalmic sockets or cicatrizing conjunctival diseases, infected sockets, and patients with history of orbital irradiation. Patients were allocated into either group using alternating choice technique. First, patients were categorized depending on the etiology of atrophia or evisceration. Then, coin tossing was done for the first patient in each category to allocate him in either group. Alternating choice was then applied in each category for their patients to get homogeneous groups regarding the etiology.

All patients underwent a thorough preoperative workup. A detailed examination of the socket was done to assess gross malposition of eyelids, superior sulcus deformities, presence of fibrous bands, signs of infection, size of the palpebral aperture, IF depth, and any gross bony deformity or contracture. IF depth of the socket was measured using a transparent scale. The patient was asked to look up for lower fornix measurement because this position was preferred so as to get maximum depth of the IF.

Surgical Technique

In patients of both groups, preoperative preparation of the patients consisted of taking a swab for culture and sensitivity from the socket and starting local antibiotic drops till the cultures were sterile. Antiseptic mouth washes were given 3 times a day to all the patients for 3 days before surgery. Patients were operated under general anesthesia with nasotracheal intubation and packing of the oropharyngeal area. All surgeries were done by the first 2 authors (S.S.M. and H.M.E.).

The socket was washed with saline and antibiotic and eyelids were separated by a retractor. The incision was made in the center of the socket from canthus to canthus; fibrous tissue was excised along with the fibrous bands. Then pressure hemostasis was done, the use of cautery was preferably avoided. In patients of group B, small pieces of surgical sponges soaked in 0.02% MMC were placed under the conjunctival flaps of the surgical wound and in the surgical bed for 5 min. After the sponges were removed, the area was irrigated with a balanced salt solution.

In patients of both groups, a mucous membrane graft was taken from the lower lip or cheek. The aim was to get a graft that was 30% larger than the size of the defect. The area of the graft to be taken from the mucous membrane was first marked by gentian violet and later on infiltrated with 2% xylocaine with adrenaline 1:100,000 so as to obtain a good plane of cleavage and achieve the hemostasis. Care was taken not to injure the opening of Stensori's duct while taking the graft from the cheek area, and not to damage the frenulum and keeping at least 2 mm of the mucous membrane around which helps in suturing after proper undermining of the edges. A round-bladed No. 15 Bard Parker knife and rounded tip curved scissors along with the support from the pulp of the index finger helped in the clean dissection.

The graft was then placed in position, and 4 sutures to properly fix the graft were first applied. Then, 6/0 Vicryl interrupted sutures were used to suture the graft after ensuring proper hemostasis. Stab incisions were made in the graft to prevent any collection beneath the graft. Upper and lower fornix fixation sutures were passed keeping an adequate depth of the lower and the upper fornix. After this, a snugly fitting conformer with multiple holes was placed in the reconstructed socket so that adequate pressure is maintained on the graft and the area of the fornices. Tarsorrhaphy was done at the end of the reconstruction.

Postoperative treatment included topical antibiotics and oral analgesic for pain as required. Tarsorrhaphy sutures were removed after 1 week. The fornix-forming sutures were removed after 3 weeks. Patients were then evaluated for customized prosthesis between 6 and 8 weeks. Postoperative complications were looked for to assess the potential complications of MMC use and its effect on taking of the graft. Ability to retain the prosthesis was checked during each visit and it was considered acceptable if the prosthesis is well fit in place with no or slight tilting or rotation with blinking. All postoperative visits were done by independent examiners who were blind to the type of surgery used.

Results

This study included 40 patients divided into 2 equal groups, A (as a control group) and B (as a case group). There was no statistically significant difference between the 2 groups regarding age, sex, etiology, preoperative IF depth, time passed since evisceration, or ocular atrophy as well as time passed since last surgical interference to correct contracted socket. All patients of both groups had only 1 surgical interference to repair contracted socket with subsequent recurrence. At least 6 months should have passed between previous surgical interference and enrolment in the study. MMC was only applied in group B during contracted socket reconstruction surgery.

In this study, the mean age was 42.85 ± 21.36 years and the mean preoperative IF depth was 2.7 ± 0.98 mm in group A. In group B, the mean age was 43.4 ± 21.75 years and the mean preoperative IF depth was 3.05 ± 0.89. The most common cause for evisceration in group A was endophthalmitis (20%) and in group B it was endophthalmitis (20%) and also absolute glaucoma (20%) as shown in Table 1.

Graft shrinkage occurred earlier and appeared to be greater in group A (without MMC) compared with mucous membrane grafts associated with MMC (group B), this is clearly apparent when comparing the IF distance between both groups, in which it was insignificant in the first and third postoperative months, whereas the difference became significant (P ≤ 0.05) in the sixth postoperative month, and highly significant (P ≤ 0.005) at the end of follow-up period. Graft infection or socket granuloma was not observed in any of our cases. No significant complications were found in group B resulting from MMC use. However, wound healing took 1 week more in only 1 case of this group.

No statistical significance was found between group A and group B (with MMC) regarding postoperative IF depth after 1 month and after 3 months (P values are 0.101 and 0.15, respectively). However, statistical significance skewed up after 6 months and after 12 months (P values are 0.017 and 0.001, respectively) as shown in Table 2.

After a follow-up period of 6 months, 75% of patients in group B (with MMC) and 70% of patients in group A could maintain the prosthetic eye shell. There was no statistically significant difference between the 2 groups (P value is 1). After 12 months of follow-up period, 75% of the patients in group B (with MMC) and only 35% of group A could maintain the prosthesis. There was strong statistically significant difference (P value is 0.026) as shown in Table 3.

Discussion

Contracture of the eye socket leads to prosthetic fitting difficulties, cosmetic problems, and may become a source of chronic discharge and irritation for anophthalmic patients, or patients with an atrophic globe. ⁹ Several grafting materials have been used to manage contracted socket, including buccal mucosa grafts,^8,10 which remain the most widely used method for the treatment of the foreshortened conjunctival fornices. ¹¹ However, poor rigidity of the mucosa membrane and postoperative mucosal contracture can increase the rate of recurrence. ¹² As well, it is difficult to harvest large mucosal flaps, otherwise, donor site morbidity may occur. ¹³

The antimetabolite use to prevent eye socket contracture is a potentially new technique. MMC and 5-FU are 2 of these antimetabolites that are widely used in ophthalmic surgery. For example, MMC is used in prevention of recurrence after excision of primary nasal pterygium and in subscleral trabeculectomy in glaucoma management.^4,14 5-FU as well is one of the antimetabolites widely used in ocular practice. It is a pyrimidine analogue and antiproliferative drug. ⁸ Despite its antiproliferative effect, serial subconjunctival injection of 5-FU has been found to cause squamous metaplasia.^8,15 As well, using a small dose in the ocular practice may cause neurotoxicity, leading to general tonic-clonic seizures.^8,16,17

MMC is an alkylating chemotherapeutic drug and a strong fibroblast inhibitor.^4,18,19 It has been reported to cause irreversible damage in corneal and conjunctival endothelium.^4,18–20 Therefore, the use of low dose concentration of MMC (0.2 mg/mL) may avoid these side effects. Intraoperative application of MMC in the operative bed has a better effect because this will prevent the active process of fibrosis at the site of pathology directly.^4,8,14,21

In this study, we used a single intraoperative topical dose of MMC (0.2 mg/mL) in treatment of patients of the case group. At the end of the follow-up period, 15 out of 20 patients (75%) could maintain the prosthesis and this was significantly higher than those who could maintain it in the control group (35%). In a study done by Bajaj et al., they repaired 10 patients with mild to moderate contracted sockets with mucous membrane grafting. After 6 months follow-up, only 1 case was unable to retain the prosthesis (10%). Their results were better than ours, and this may be because of the type of cases in the study as our cases were all recurrent, which increase the possibility of fibrosis and subsequent contracture. ²²

In 2013, Kamal et al. performed a retrospective study on 8 patients who were injected weekly by 5-FU during the early postoperative period. ⁸ There was a strong improvement in the IF depth in 7 out of the 8 patients. In this study, in comparison with Kamal's study, we used a different antimetabolite (MMC) with a different mode of application (single intraoperative topical dose) and on a larger sample size (20 patients).

In 2012, Priel et al. performed a retrospective noncomparative study about the antimetabolite use in repair of severe socket contraction. ¹⁰ The study included 5 patients: 2 of them were injected by MMC (0.4 mg/mL) in the fornix. The other 3 were injected by 5-FU (50 mg/mL) intraoperatively and postoperatively in the clinic. All the 5 patients could maintain the prosthesis during the follow-up period without delay in wound healing.

In the current study, in comparison to Priel's study, we used MMC but in a different concentration (0.2 mg/mL) during the surgery and with a different mode of application in the case group.

In conclusion, this study shows that using intraoperative MMC (0.2 mg/mL) in contracted socket reconstruction plays a significant role in maintaining prosthetic eye. Using it will decrease the economic cost of frequent reconstructive surgeries. It will also protect the patients of the complications resulted from the weekly sub-conjunctival injection of 5-FU. To the best of our knowledge, this study is the first to use MMC on a relatively large scale of patients with contracted socket.

However, the follow-up period was relatively short and further work is required to verify the effect of MMC on a longer follow-up period. As well, the number of cases is small and larger scale studies are required to fully investigate the issue. Meanwhile, we did not study the effect of MMC on cicatrizing conjunctival diseases as well as postirradiated sockets, which represent a great challenge to oculoplastic surgeons.