Introduction

Symblepharon is a condition with a diverse aetiology ranging from injuries and infections to oculocutaneous disorders and drugs. Whatever the cause, it can impose a significant amount of morbidity upon the patient in the form of persistent lacrimation, diminution of vision, double vision or foreign body sensation. In these eyes, it becomes imperative to treat the symblepharon to restore the normal ocular surface.

A variety of approaches have been tried for the successful surgical management of chronic symblepharon.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 However, none of these have met with unreserved success due to the various associated complications.2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13

Various materials have been evaluated as substitutes for ocular surface epithelia following excision of the symblepharon. A popular alternative was the use of mucus membrane grafts obtained from the buccal cavity, nose, hard palate, and maxillary sinus for the above purpose. However, these suffer from the disadvantages of difficulty in harvesting, limited availability, persistence of reddish colour long after surgery, and unacceptable complications at the donor site.2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 16

Nonporous PTFE has been explored as an alternative, as it does not have a limitation of size, is chemically and biologically inert, and resistant to infection. However, it is associated with a relatively high extrusion rate (∼20%) and may permit proliferation of submucous fibrous tissue in cicatricial inflammatory diseases, leading to eventual failure.11

Postoperative subconjunctival fibrosis has been identified as the commonest cause of failure of the surgery and recurrence of the symblepharon. Beta irradiation and antimitotic agents have been used both intra- and postoperatively to reduce this fibrotic response. However, specific indications, regimens, and delivery systems for their use have not been established. Moreover, they have been associated with serious complications including scleral necrosis and delayed epithelization.12, 13

Amniotic membrane transplantation (AMT) is a relatively recent approach to the surgical management of chronic symblephera. The basis of its use rests on unique properties of the membrane, which have shown to be beneficial in this scenario.12

The amnion serves as ‘transplanted basement membrane’ acting as a new healthy substrate suitable for proper epithelization. This basement membrane helps migration of epithelial cells, reinforces adhesion of basal epithelial cells, promotes epithelial differentiation, and prevents epithelial apoptosis.17, 18, 19 The membrane has been successfully used for culturing rabbit oral mucosal cells20 as well as corneal/limbal epithelium for transplanting in patients with limbal deficiency.21

The membrane produces various growth factors including basic fibroblast growth factor, hepatocyte growth factor, and transforming growth factor β (TGF β)12 that can stimulate epithelization22, 23, 24 and act as promoters of epithelization and inhibit protease activity.

Amniotic membrane does not express HLA-A, B or DR antigens and hence immunological rejection does not occur after its transplantation.23, 24

In addition it has antifibroblastic properties as it induces a downregulation of TGF β signalling, responsible for fibroblastic activation in wound healing.25, 26 This leads to an inhibition and arrest in fibroblast proliferation, following contact with normal substrate, and prevents the occurrence of subconjunctival fibrosis, which is usually the cause of recurrence of symblephera after surgery.

In addition, it becomes indistinguishable from subconjunctival tissue, once covered with conjunctiva, thus offering excellent cosmesis. It forms a continuous collagenous sheet on the sclera and functions as a mechanical barrier, keeping potentially adhesive surfaces apart.

These properties have prompted the use of these membranes in patients with ocular chemical and thermal burns,27 recurrent pterygia associated with symblepharon,28 after pterygium excision, in corneal surface reconstruction,12 revision of leaking blebs after glaucoma surgery,29, 30, 31 bullous keratopathy,32 after surgical treatment of band keratopathy,33 symptomatic conjunctivochalsis,34 ulceration of the cornea and sclera,35 post excimer to reduce corneal haze,36, 3 etc, and more recently for the treatment of symblepharon.38

Our aim was to study the results of amniotic membrane transplantation in the surgical treatment of symblepharon, to determine the rate of re-epithelization of the amniotic membrane graft, assess incidence of the intra- and postoperative complications encountered, and to observe the recurrence rate of cicatrization following AMT in these eyes.

Materials and methods

A total of 20 eyes of 18 patients were operated upon in this interventional, noncomparative, prospective study. All eyes included presented with stage II or III symblepharon (Tauber's14 staging) of varied aetiology, including chemical, thermal, and mechanical injuries, congenital, iatrogenic or post-surgical, and symblephera secondary to oculocutaneous syndromes or ocular cicatrizing disorders.

Patients with acute infection or inflammation at the operative site, those with active Stevens–Johnson's syndrome (SJ syndrome) or pemphigoid, patients with Stage I symblepharon,14 and those presenting with ankyloblepharon were excluded from the study.

In all the patients selected, a detailed preoperative ocular and systemic evaluation was undertaken, including an assessment of the ocular motility, diplopia charting, and staging of the symblepharon by Tauber's14 method. The presence of dry eye, if any, was documented (defined as a Schirmer's value less than 5 mm after 15 min). The indication for which the patient was booked for surgery was also noted.

Preparation of the membrane

The placental membranes were obtained from mothers seronegative for Hepatitis B, and C, Syphilis, and HIV at elective caserean section. The translucent amnion was separated from the underlying thick, vascular chorion and preserved at +4°C by the method outlined by Dino et al.39 A marking 6-0 silk suture was used to differentiate the rough mesenchymal from the smooth epithelial surface. All membranes obtained were used within 24 h and precautions were taken to keep the membrane and the media sterile at all times.

Surgical procedure

Surgery was performed under either general or peribulbar anaesthesia.

The eye to be operated was cleaned and draped and adequate exposure obtained with a lid speculum.

The conjunctiva was incised horizontally along the ends of the symblepharon and undermined from the Tenon's fascia to allow the tissue to retract to its normal anatomical position. The adjacent extraocular muscles were identified and hooked. The subconjunctival fibrous tissue was excised to the maximum extent possible and any adhesions with the muscle sheaths were released. The exposed sclera was lightly cauterized. Corneal involvement was cleared by superficial keratectomy with a diamond knife.

An amniotic membrane graft, approximately 20% larger than the corresponding conjunctival defect, was obtained from the preserved membranes. The graft was placed epithelial side up on the scleral surface and secured to the recipient conjunctival edge with 8/0 Vicryl sutures. Care was taken to anchor the graft to the bed with episcleral sutures. Fornix-forming sutures with 4/0 silk were used in selected eyes.

The eye was patched postoperatively and the pad removed the next day. The patient started on topical Ofloxacin every 4 h in the operated eye. Topical prednisolone acetate 1% every other hour was commenced once the corneal epithelial defect healed (confirmed by fluorescein staining). These drops were continued for 2 weeks and then tapered off over the next few weeks.

The fornix-forming sutures were removed after 3 weeks.

Postoperative evaluation

The patients were reviewed on the immediate postoperative day, weekly for the first 3 weeks and then monthly till the end of 1 year.

The parameters assessed at every visit included the best-corrected visual acuity, ocular motility, and diplopia charting, evaluation of the lid margin contour, and the presence of postoperative inflammation or infection.

The graft was evaluated with respect to its position, colour, degree of epithelization, and the presence or absence of subconjunctival fibrosis.

Recurrence of the symblepharon (if any) was documented and staged at every visit.

Any significant postoperative complications were recorded.

Successful outcome of the surgery was defined as a healthy fully epithelized graft area with no recurrence of the symblepharon (or recurrence of a stage lesser than or equal to IIa) at the completion of follow-up, affording no functional or cosmetic disability to the patient.

Results

The study group comprised 20 eyes of 18 patients, all of whom underwent symblepharon excision with AMT. The mean age was 26.3 years (10–70) and the sex ratio, 11 males to seven females. The demographics and the clinical data of the patients are summarized in Table 1.

Table 1 Clinical and demographic data
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The common causes included recurrent pterygium (five), acid burns (one), alkali burns (five), Stevens Johnson (SJ) syndrome (four), thermal burns (three), and congenital symblephera (two).

The indications for surgery were diplopia (two), as a prerequisite for penetrating keratoplasty (eight), entropion (five), squint (two) mechanical ptosis (one), and cosmetic (two). Out of the total operated eyes, 10 (ie 50%) had been operated one or more times previously.

On initial examination, four patients had a Schirmer's I value less than 5 mm in 10 min, signifying a dry eye, the cause being SJ syndrome in three and thermal burns in one patient. Two patients complained of double vision preoperatively due to associated restrictive strabismus.

After surgery, the amniotic graft re-epithelized completely in all eyes, beginning at the edges of the graft at a mean time period of 15.5 days (12–18) and completely covering the graft in a mean time period of 23.3 days (20–27). The regenerated conjunctiva was indistinguishable from the surrounding conjunctival epithelium on slit-lamp examination.

The immediate postoperative period in most eyes was largely unremarkable with a rapid decline in the amount of postoperative inflammation, as evidenced by diminishing conjunctival congestion and chemosis. However, four eyes (20%) showed signs of persistent inflammation lasting beyond 2 weeks, which necessitated vigorous anti-inflammatory therapy in the form of frequent topical steroid drops (prednisolone acetate hourly) for the first 2 weeks and then tapered gradually.

One patient who had been operated upon five times in the same eye previously for recurrent pterygium showed an exuberant fibroblastic response with complete recurrence of the symblepharon as early as 3 weeks postoperatively. We obtained a biopsy from the edge of the graft to study the nature of the response.

The histopathological evaluation revealed mild to moderate acute on chronic inflammation of the transplanted amniotic membrane. The newly proliferated conjunctiva showed areas of congestion with neovascularization and fibrosis (Figures 1, 2, 3, 4, 5 and 6 and 7).

Figure 1
figure 1

Preoperative photograph showing a patient with an anterior staphyloma and Stage III(c) symblepharon following mechanical injury.

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Figure 2
figure 2

Postoperative clinical photograph at 6 months showing healthy well-epithelized graft with no recurrence of the symblepharon. The patient subsequently underwent an optical penetrating keratoplasty.

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Figure 3
figure 3

A medial symblepharon that formed following pterygium excision and led to severe restriction of ocular motility and binocular diplopia.

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Figure 4
figure 4

Postoperative photograph at 6 weeks, with marked improvement in ocular motility and no diplopia.

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Figure 5
figure 5

Recurrent pterygium Stage III b(1) symblepharon with two previous corrective surgeries.

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Figure 6
figure 6

The same patient as Figure 5, 2 weeks postoperatively, with partial re-epithelization of the graft.

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Figure 7
figure 7

Photomicrograph showing severely inflamed conjunctival epithelium with vascularization, hyalinization, and subconjunctival fibrosi.

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No graft was rejected in our mean observation period of 53.3 weeks (32–80 weeks).

We noticed a significant improvement in ocular motility in 100% (18) of the patients with restricted preoperative movements, and complete remission of diplopia in all the patients (two) complaining of it preoperatively.

We did not observe a statistically significant improvement in visual acuity after surgery due to the poor corneal transparency in the eyes that were undergoing preparatory symblepharon release before penetrating keratoplasty.

We observed recurrence of symblepharon in eight out of the 20 eyes operated (40%).

However, in two of these patients, the recurrence was of stage IIa that did not pose any functional problems for the patient. Thus, our failure rate was only 30%.

All (four) the eyes that had documented dry eye preoperatively failed and four of the six eyes that failed had been operated on at least once earlier.

Discussion

The use of amniotic membrane in the reconstruction of conjunctival surface is not a novel concept, with the earliest reports dating back to the 1940s.40 However, after ensuing decades of relative obscurity, interest has resurfaced again in the use of amniotic membrane in the treatment of ocular surface disorders.41, 42, 43 We evaluated the outcome of AMT for reconstruction of the conjunctival surface following surgical treatment of chronic symblephera in 20 eyes of 18 patients in our study.

In our study, the surgical outcome of AMT after symblepharon excision was fair with only six eyes out of the 20 operated failing to meet the criteria for a successful surgical outcome as defined in the protocol.

All the patients who had preoperative severe dry eye (four), that is, Schirmer's value less than 5 mm in 15 min responded very poorly to the surgery with a 100% failure rate. Three of these eyes belonged to patients suffering from SJ Syndrome and one secondary to extensive thermal injury, both of which caused extensive damage to the ocular surface and disruption of the tear film. It has been demonstrated previously that decreased tear secretion is a significant risk factor of surgical failure in SJ Syndrome, with a failure rate of 68.4% that compared with 100% in our study.44

Preoperative tear function is a strong determinant for successful ocular surface construction, as tears are essential for the proliferation and differentiation of epithelial cells.44 Tears have been shown to contain many important epithelial modifying factors, such as epidermal growth factor,45 vitamin A,46 and TGF β-1 and β-2. Decreased tear production not only causes desiccation, but also nutritional deprivation in ocular surface epithelia and accumulation of cytotoxic components in the ocular surface.

The amniotic membrane provides only a basement membrane for epithelial proliferation, but cannot replace the tear film, which may explain the high rate of failure in these eyes. Thus, it acts as a substrate but not as substitute for healthy conjunctiva.

All of these eyes exhibited an intense and prolonged postoperative inflammatory response. The failure in these eyes may thus also be related to the elaboration of collagenases as a result of the inflammation that can cause early degradation of the amniotic membrane before epithelization is complete.

Measures used to manage ocular surfaces in patients with deficient tear films postoperatively include autologous serum eye drops, hyaluronic acid eye drops, and punctual occlusion. However, no prospective study has conclusively proved the superiority of any one method over the others.

A contributory factor determining the success of the procedure appeared to be previous conjunctival surgery. Four of the six eyes that failed and six out of the eight eyes that recurred had previous conjunctival surgery though there seemed to be no statistically significant correlation between the severity of postoperative fibrotic response and the number of previous surgeries. The recurrence in these eyes was probably due to a greater subconjunctival fibroblastic response that led to eventual recurrence of the symblepharon.

We conclude that AMT after symblepharon release is a safe and effective procedure with a 100% rate of epithelization and no significant postoperative complications. We observed a 30% rate of failure, the success of the surgery being limited by the underlying ocular pathology, and previous surgical profile. Patients suffering from severe preoperative dry eye or those who have undergone multiple previous conjunctival surgery may not be best suited to AMT alone, but may need a supplementary medical or surgical procedure.