Corneal perforation, a potentially devastating complication, can result from numerous conditions that precipitate corneal melting. Numerous causes include microbial keratitis, ocular surface disease, and autoimmune disorders, in addition to trauma where penetrating injuries occur. It is associated with significant ocular morbidity and warrants prompt intervention, both to restore globe integrity and to minimize the risk of secondary complications including endophthalmitis, choroidal hemorrhage, and glaucoma. Various management options have been described in the literature, with multi-staged procedures that are often required to facilitate visual rehabilitation. These procedures range from temporizing measures such as corneal gluing to corneal transplantation, with decision making, guided by the location, size, and underlying etiology of the perforation.
Causes of Corneal Perforation
The causes of corneal perforation can be classified as either traumatic or nontraumatic, with nontraumatic perforation being further divided into infectious or noninfectious causes. Infectious perforation can occur secondary to bacterial, fungal, viral, or parasitic infection while noninfectious etiologies include ocular surface or autoimmune disease. Causative ocular surface conditions include keratoconjunctivitis sicca (KCS) or Sjogren syndrome (SS), while autoimmune conditions leading to perforation include peripheral ulcerative keratitis (PUK) secondary to conditions such as rheumatoid arthritis (RA), Mooren's ulcer, Wegener's granulomatosis, and relapsing polychondritis.
Tissue adhesives may be used to manage small corneal perforations. Currently, nonbiologic (cyanoacrylate) and biologic (fibrin glue) adhesives are available.
At present, the following formulations are available for use:
- Indermil (butyl-2-cyanoacrylate; Sherwood, Davis and Geck, St Louis, MO, USA)
- Histoacryl (butyl-2-cyanoacrylate; BBraun, Melsungen, Germany)
- Histoacryl Blue (N-butyl-2-cyanoacrylate; BBraun, Melsungen, Germany)
- Nexacryl (N-butyl-cyanoacrylate; Closure Medical, Raleigh, NC, USA)
- Dermabond (2-octyl-cyanoacrylate; Closure Medical, Raleigh, NC, USA).
Cyanoacrylates are ester derivatives of cyanoacrylic acid. In 1960, Refojo et al. first described the technique of treating corneal perforations using cyanoacrylate glue. This method is best suited to perforations that measure less than 3 mm in diameter, are concave in profile, and located away from the limbus. The latter due to the poor adhesion that occurs between the glue and the conjunctival tissue, and the tendency for the adhesive to dislodge when applied in this location.
Cyanoacrylates undergo polymerization upon contacting water or weak bases, causing them to harden. Short-chain derivatives are strongest, and as such, the tensile strength of N-butyl cyanoacrylate compounds is greater than that of octyl-cyanoacrylates. Dry conditions are required for optimal polymerization of butyl derivatives, with peak bonding strength occurring at 2 min.
Derivatives with longer alkyl side chains enjoy the best biocompatibility profile, due to increased production of toxic byproducts that occur with the degradation of shorter alkyl side chain compounds. Similarly, histotoxicity also increases with tissue vascularity. Cyanoacrylates are also bacteriostatic, particularly against gram-positive organisms including Staphylococcus aureus, Streptococcus pneumoniae, and group A Streptococci, an effect that is possibly due to the absence of a lipopolysaccharide capsule among these pathogens. Similarly, the bacteriostatic activity increases with decreasing alkyl side chain length.
Fogle et al. demonstrated that the application of cyanoacrylate adhesive to an ulcer bed disrupts stromal melting, in both infective and noninfective cases. Large numbers of polymorphonuclear leucocytes, which have potent collagenolytic and proteolytic activity, are present in active corneal ulcers and promote corneal melting. These leucocytes are stimulated by the interaction between re-epithelializing epithelium and the subjacent keratocytes. Cyanoacrylates inhibit re-epithelialization and consequently inhibit the polymorphonuclear leucocytic infiltration in the diseased area.
Techniques of application
While glue can be applied at the slit lamp, it is preferable to perform the procedure in the operating theatre, using the operating microscope under aseptic conditions. Using topical or local anesthesia, an eye speculum is used to gain adequate exposure of the ocular surface, with a noncompressing lid speculum being preferred.
Various techniques have described the effective application of cyanoacrylate adhesive to corneal perforations. The glue can be drawn into a syringe using a 20G needle, before being applied as a drop to the corneal defect using a 27G or 30G cannula. This allows a small amount of glue to be applied in a controlled manner. The application of glue must be performed rapidly to avoid polymerization and hardening of the glue in the cannula. Once in contact with the cornea, the glue spreads to cover the perforation, forming a hardened seal within a few seconds. Additional glue can then be applied as needed in the event of a persistent leak. Following this, a bandage contact lens (BCL) is used to cover the site. The adherence of the glue, and thus the success of the procedure, can be improved by ensuring that the site of gluing is debrided of necrotic epithelium beforehand and kept dry throughout the procedure.
In cases where the iris tissue plugs the perforation or where the anterior chamber collapses, it is advisable that the anterior chamber is reformed using viscoelastic material or an air bubble to prevent contact between the glue and intraocular structures.
Moreover, an alternate method of utilizing a disc made out of sterile plastic drape to apply the glue, has also been described, wherein, a disc of drape is cut and a drop of glue is placed on it. The disc is then placed over the perforation, and the glue is allowed to dry before a BCL is inserted. This gives the adhesive a smoother surface to adhere to and prevents the inadvertent instillation of glue into the anterior chamber.
A modified version of this technique, as described by Khalifa et al., involves gluing a disc of sterile plastic drape over the perforation using cyanoacrylate, similar to a tectonic patch. This has the advantage of avoiding direct contact between the glue and anterior chamber thus, limiting any potential immune response elicited by the glue. In an attempt to glue defects larger than 3 mm, a number of other modified techniques have been described. Moschos et al. described using a 10–0 nylon suture, placed as a mesh across the defect, over which the glue is applied while Gandhewar et al. described placing a double layer of sterile plastic drape between the glue and the anterior chamber to form a barrier which bridges the defect site.
Regardless of the technique of application, the eye must be closely examined after gluing to ensure that no leaks are present, and that reformation of the anterior chamber occurs [Fig. 1a and b]. However, in most cases, the glue patch only temporarily occludes the perforation; and during this time wound healing has the opportunity to occur. Nevertheless, the literature reports this to be an effective method for managing small perforations, the outcomes following gluing may vary in different studies. In one series, Setlik et al. reported that over 40% of cases healed following the use of tissue adhesive alone while Hirst et al. reported both lower enucleation rates and improved visual outcomes with the use of tissue adhesives.
Complications and adverse effects
The primary concern regarding cyanoacrylate use is its stromal, endothelial, and lenticular toxicity when directly contacting the cornea or lens. One difficulty with accurately quantifying the toxic effects of cyanoacrylate is delineating the effects of the glue versus the underlying disease process. Other complications can include raised intraocular pressure, possibly secondary to inflammation affecting the trabecular meshwork, (1) and microbial keratitis, especially with prolonged use. Moreover, it is uncertain if the latter is due to the glue itself, given that it has antimicrobial properties, or due to the presence of a BCL. As such, close observation of patients is essential, particularly those who are immunocompromised. It is hoped, that as newer derivatives with longer alkyl side chains are developed, the biocompatibility of cyanoacrylate glue improves, leading to fewer adverse effects.
Fibrin glue is a biologic product containing fibrinogen and thrombin. It is completely biodegradable and induces minimal stromal inflammation or tissue necrosis, therefore, less toxic than cyanoacrylate, providing a more suitable environment for healing. In general, thrombin catalyzes the conversion of fibrinogen to fibrin in the coagulation pathway, resulting in the formation of a hemostatic plug. When applied to a corneal perforation, this hemostatic plug forms an effective sealant, and when used for defects up to 2 mm is as effective as cyanoacrylate. However, for defects between 2–3 mm, cyanoacrylate appears to be superior. Due to its role in the coagulation pathway, fibrin plays an integral role in wound healing. Intrinsically, it enhances scar tissue formation when used for corneal perforations and is associated with a reduced incidence of corneal vascularization and giant papillary conjunctivitis. However, in particular, fibrin glue degrades more quickly than cyanoacrylate glue, does not have antibacterial properties, and bovine-derived products may transmit prion or viral disease.
Superior forniceal conjunctival advancement pedicels, such as Gundersen or Cies's racquet conjunctival flap, are typically used for indolent, nonhealing, corneal ulcers, and impending perforations. These flaps require extensive conjunctival dissection and obscure the cornea postoperatively. They promote extensive corneal vascularization which facilitates corneal healing but simultaneously increases the risk of graft rejection if one is performed at a later stage.
As suggested by the name, a superior forniceal conjunctival flap is mobilized on a pedicle and transferred to cover the defect. This biological patch provides trophic factors, mechanically protects the cornea, and offers analgesic effects. In addition to corneal vascularization, complications include, flap perforation or fenestration, and partial or complete flap displacement, particularly when managing central lesions.
Amniotic membrane transplant
In 1997, Lee and Tseng were the first to propose the use of amniotic membrane transplantation (AMT) for the treatment of corneal epithelial defects. Chen et al. subsequently reported the effectiveness of AMT in severe neurotrophic keratopathy and studies have since described the successful use of AMT in the management of corneal perforations. The technique allows rapid restoration of corneal integrity, avoiding the need for urgent keratoplasty.
AMT is particularly useful in cases of central perforation where conjunctival flaps have a greater risk of displacement. Furthermore, conjunctival flaps used in large perforations carry an increased risk of nonadherence to the cornea, resulting in hypotony and predisposing the eye to endophthalmitis. AMT also induces less vascularization than conjunctival flaps, increasing the chance of successful keratoplasty in the future.
Properties of amniotic membrane
Amniotic membrane has several properties that make it suited for use in the management of corneal perforations. Amniotic membrane epithelium contains growth factors including hepatocyte growth factor, keratocyte growth factor, and epidermal growth factor. The presence of these trophic factors aid epithelial healing by promoting differentiation and migration of epithelial cells that are in contact with the amniotic membrane. Inhibitory proteases released by the amniotic membrane also induce apoptosis of local inflammatory cells, reducing the risk of corneal melt. Reports have also suggested that stromal tissue is synthesized from the amniotic membrane in cases involving deep ulcers or descemtocoeles.
Surgical technique and outcomes
Multilayered AMT is preferred in the management of deep corneal ulcers or perforations. This involves filling the defect with multiple pieces of amniotic membrane before covering the entire cornea with a final layer of transplanted tissue. The transplanted membrane can then be secured using sutures or fibrin glue. Using this technique, Rodríguez-Ares et al. reported a 100% healing rate for micro-perforations and an almost 75% rate of closure for perforations up to 1.5 mm in diameter. AMT in combination with fibrin glue has also been demonstrated to be effective at managing defects up to 3 mm in size, while piled, multilayered AMT, forming an augmented patch has been used in combination with fibrin glue to treat defects greater than 3 mm.
Tenon's patch graft
The use of Tenon's capsule has been described in the repair of traumatic scleral perforations and leaking trabeculectomy blebs. Recently, the use of a Tenon's patch graft has been described in the management of large corneal perforations, measuring up to 6 mm, where tissue adhesive is not suitable. Anatomically, Tenon's capsule arises 2 mm posterior to the limbus, and it is postulated in such a way that it has the ability to produce autologous fibroblasts and connective tissue, allowing it to be incorporated into the host's corneal tissue.
Harvesting the Tenon's graft
Incisions are made posterior to the scleral insertion of Tenon's capsule, in the inferotemporal and inferonasal quadrant, and a portion of the capsule excised. It is advised that the size of the graft is slightly larger than the size of the corneal defect. The site of harvest can simultaneously be used to drain choroidal effusions, which may be present in cases where a large perforation is present.
Applying the Tenon's patch graft
Before applying the graft, the cornea is debrided, removing debris, and the epithelium adjacent to the perforation. The graft is then ironed into a thin layer and placed over the defect before being secured in place using either tissue adhesive or sutures. Following this, the anterior chamber is reformed using an air bubble, with the fluid being avoided during this process to reduce the risk of malignant glaucoma. As healing occurs, the Tenon's graft is incorporated into the corneal scar and the success of this procedure is up by 75%, as reported by Korah et al. [Fig. 2a and b].
Tenon's capsule is an autologous transplant, hence no immune response is evoked and thus tissue rejection does not occur. Furthermore, unlike corneal grafting or AMT, this tissue does not rely on donor tissue or it's associated infrastructure such as eye banks, and thus supply can be more readily guaranteed. Lastly, as there are no heterologous antigenic sensitization, corneal grafting is more likely to succeed if performed at a later stage.
Large corneal perforations are not amenable to the abovementioned treatment modalities and often require a tectonic keratoplasty. Tectonic corneal transplants restore globe integrity by filling corneal stromal defects. Surgical techniques such as full-thickness keratoplasty, lamellar keratoplasty, and corneal patch grafts have been described, and are chosen depending on the size, depth, location, and cause of perforation. In recent years, lamellar keratoplasties have become increasingly popular owing to the lower rate of graft rejection compared to penetrating keratoplasty (PK).
Corneal perforations secondary to infective keratitis
Therapeutic keratoplasty not only restores the integrity of the globe but also reduces the microbial and necrotic tissue load, and thus reduces the associated toxins and enzymes which contribute to the progression of infective keratitis and corneal stromal melt. The ideal timing of the surgery varies significantly among the patients. Where the anterior chamber is flat, it is recommended that grafting needs to be performed within 24-48 hours, to minimize long-term complications. However, Nobe et al. reported improved graft survival in cases where keratoplasty was delayed, suggesting that where the anterior chamber is maintained, this approach should be pursued. Tectonic epikeratoplasty, typically used in the management of sterile corneal melt, has also been used in the management of infectious keratitis. However, Bull et al. concluded that this procedure was inferior to that of penetrating keratoplasty in the above context.
The trephination of host tissue is technically difficult in the absence of tissue rigidity and, as such, a Flieringa ring may be needed to provide scleral support intraoperatively. All necrotic tissue should be excised with a 1 mm margin of healthy tissue, to ensure a healthy donor bed free of infection. A superficial mark is made with a trephine and used as a guide to excise the diseased corneal tissue. Once the tissue is excised, anterior and posterior synechiae are gently lysed before suturing the donor cornea in place [Fig. 3a and b].
Corneal perforation with iris plugging
It is not uncommon for the iris tissue to plug a perforation and form a pseudocornea. The presence of iridocorneal adhesions increases the chances of iris tissue avulsion and hemorrhage during surgery. This results as the removal of adherent corneal tissue requires a greater force than the iris tissue can withstand, leading to iris tears and bleeding. Vajpayee et al. described a technique of lamellar separation for such cases involving initial debulking of the cornea using lamellar dissection, followed by entry into the anterior chamber. This allows gentle separation of the deep corneal lamellae from the adherent iris tissue, helping to preserve iris tissue and reduce the risk of subsequent complications including anterior synechiae, secondary glaucoma, and iris defects, in turn, improving graft survival [Fig. 4a and b].
Corneal perforations in sterile melts
Tectonic epikeratoplasty (TEK) is a procedure that has been described in the management of sterile corneal melts [Fig. 5]. In this procedure, donor corneal tissue is placed over the perforated cornea and sutured to the surrounding sclera after a 360° peritomy has been performed. It is then left in place to allow the underlying site of stromal melt to heal. Donor corneas that are unsuitable for use as an optical graft owing to poor endothelial cell count or stromal scarring may be used for this purpose, giving this procedure an advantage from a healthy resource perspective. Similarly, Lazaridis et al. used ethanol-preserved donor corneal stroma, derived as a by-product following endothelial keratoplasty graft preparation, and reported good outcomes.
As described by Paufique in 1950, lamellar corneal patch grafting can also be used in the management of corneal perforations and descemetocoeles. Sutured corneal patch grafts [Fig. 6a and b] offer greater structural integrity compared to tissue adhesives in cases of large perforations and are visually less disabling than cyanoacrylate glue in central perforations. Patch grafting also removes necrotic tissue that itself is a source of collagenases and drives stromal melting.
The use of glycerol-preserved corneas for patch grafts has also been described. Chu et al. used corneas preserved in Optisol-GS and reported favorable results. In this study, donor corneal tissue, remaining after lenticule preparation for descemet-stripping automated endothelial keratoplasty (DSAEK), was used. Similarly, Bhandari et al. used lenticules extracted during small incision lenticule extraction (SMILE) for micro-perforations in seven patients and reported successful results at 3 months postoperatively. Jiang et al. conducted a similar study with SMILE lenticules and followed up 22 eyes for 6 months, with globe integrity achieved in all cases in their series.
Peripheral corneal perforations
Several procedures have been described for dealing with peripheral perforations and corneal thinning disorders.
Corneal wedge resection
As described in the management of pellucid marginal degeneration (PMD), this technique involves excising the cornea in the region of peripheral thinning, before filling the resultant defect with a segment of healthy donor corneal tissue. It is effective in patients with small areas of corneal thinning where sutures do not affect the visual axis. Common complications include loose sutures, vascularization, and against-the-rule astigmatism.
Crescentic lamellar keratoplasty
This procedure is used in cases where there is significant peripheral thinning such as Terrien's marginal degeneration (TMD) or Mooren's ulcer. After preparing the host bed, a ring-shaped lamellar graft is sutured to the peripheral cornea. Moreover, successful surgery using both cryopreserved and glycerin-preserved tissue has been reported.
Copy and fix technique
The copy and fix technique for peripheral corneal perforations involves marking the area to be excised on the host cornea with a marking pen. The donor corneoscleral rim is placed over the marked area and the exact shape is traced on it. The graft is then harvested along the marked lines and fixed in place with sutures.
Other procedures including tuck-in lamellar keratoplasty, large penetrating keratoplasty, and corneoscleroplasty have additionally been described in the management of peripheral perforations.
Corneal perforations and subsequent scarring are a major cause of corneal blindness worldwide. A shortage of donor corneas available for transplantation has prompted research into the production and use of bioengineered tissue. Collagen is a biocompatible and biodegradable substrate that has been used to fabricate artificial corneal tissue. However, owing to the highly hydrated nature of collagen, collagen-based hydrogels are structurally weak and difficult to manipulate. While compressing collagen hydrogels ensures to improve their mechanical properties, these materials are still too weak for clinical use. Thus, plastic compressed gels and electrospun constructs have been developed to overcome this issue with promising results.
The management of a corneal perforation depends on the size, shape, location, and cause of the lesion. Smaller lesions may be managed with tissue adhesives, Tenon's patch grafting, or amniotic membrane transplantation. Larger perforations, however, may need urgent keratoplasty. Ongoing advances are being made towards the use of lamellar corneal tissue to reduce the rate of rejection and improve clinical outcomes.
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Conflicts of interest
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Know the Authors
Dr Rashmi Deshmukh
Rashmi Deshmukh was trained in ophthalmology at JIPMER, Pondicherry, where she received the Best Resident Gold Medal. She pursued RGUHS-accredited Cornea and Refractive Surgery fellowship at Narayana Nethralaya, Bangalore, under the mentorship of Dr Rohit Shetty, where she was part of several path-breaking studies that brought her several accolades. She was a faculty on the Cornea Service at Centre for Sight, New Delhi for two years, and is currently a cornea fellow at the University of Nottingham, UK under the preceptorship of Prof Harminder S Dua. She is the recipient of IJO Honour Award for Peer Review 2019, IJO Silver Award for an outstanding publication 2019, Best Paper APACRS 2017, Travel Grant ARVO 2017, KC Singhal Best Paper AIOS 2017, Best Paper APACRS 2016, and Best Paper KOS 2016. Rashmi has published about 20 peer-reviewed manuscripts and is currently the Assistant Editor of Indian IJO.
Dr Louis Stevenson
Louis Stevenson is a junior doctor currently working with Lions Outback Vision. This organisation provides ophthalmology services to remote Western Australia, using a mobile clinic to travel between population centres. This has allowed patients to access specialist eye care in regions where this was previously not possible. In 2020, Louis is moving to Melbourne, Australia to commence ophthalmology training at the Royal Victorian Eye and Ear Hospital.
Prof Rasik Vajpayee
Rasik Vajpayee is one of the world's leading experts in the field of corneal and cataract surgery. He has been the Head of Corneal, Cataract and Refractive Surgery units of the Dr Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi (1998-2013) and of Royal Victorian Eye and Ear Hospital, Melbourne, Australia (2006-2011). Besides innovating many cataract and corneal surgery techniques, he has pioneered the use of single donor cornea for multiple patients. He is the recipient of a number of awards around the world, including several orations and fellowships and has published/edited 14 books, and more than 365 research papers.
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