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   Table of Contents      
ORIGINAL ARTICLE
Year : 2006  |  Volume : 54  |  Issue : 2  |  Page : 111-116

Low dose Mitomycin-C in severe vernal keratoconjunctivitis: A randomized prospective double blind study


Department of Ophthalmology, Post Graduate institute of Medical Education and Research, (PGIMER), Chandigarh, India

Correspondence Address:
Arun K Jain
Dept of Ophthalmology, PGIMER, Sector 12, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0301-4738.25832

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  Abstract 

Purpose: To study the efficacy and safety of low dose topical Mitomycin C (MMC) in severe Vernal keratoconjunctivitis (VKC).
Design: Placebo controlled double masked randomized clinical trial.
Materials and Methods: Twenty-eight patients with severe VKC were randomly assigned to receive either topical MMC (0.01%) (n=17) or distilled water (n=11) three times daily for a period of two weeks. Signs and symptoms were recorded on day of presentation and at the end of treatment period (2 weeks). Mann Whitney test was used to analyze the signs and symptoms in the two groups.
Results: No statistically significant difference was observed in terms of severity of symptoms at presentation. At two weeks patients in the MMC group showed significant decrease in tearing, foreign body sensation, discharge, hyperemia, punctate keratitis, limbal edema and trantas spots. No adverse effect of MMC was observed.
Conclusion: Short term low dose topical MMC is an effective and safe drug to control acute exacerbations in patients of severe VKC refractory to conventional treatment.

Keywords: Mitomycin-C, vernal keratoconjunctivitis.


How to cite this article:
Jain AK, Sukhija J. Low dose Mitomycin-C in severe vernal keratoconjunctivitis: A randomized prospective double blind study. Indian J Ophthalmol 2006;54:111-6

How to cite this URL:
Jain AK, Sukhija J. Low dose Mitomycin-C in severe vernal keratoconjunctivitis: A randomized prospective double blind study. Indian J Ophthalmol [serial online] 2006 [cited 2019 Oct 17];54:111-6. Available from: http://www.ijo.in/text.asp?2006/54/2/111/25832



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Vernal keratoconjunctivitis (VKC) is a bilateral recurrent inflammatory disorder of the conjunctiva and cornea. It is thought to be more complex than a simple type 1 hypersensitivity reaction. The trophic changes are due to enhanced fibroblast proliferation and collagen deposition in epithelium and substantia propria caused by eosinophil and mast cell degranulation.[1]

The signs and symptoms of VKC usually occur from April to August, although some patients have a perennial form of the disease.[2] The spectrum of disease differs in tropical and temperate countries.[3] The reported risk of visual loss is generally greater in tropical countries which is about 10%.[4],[5],[6],[7] Corneal morbidity along with steroid related complications may lead to permanent visual impairment. Therefore there is need for an alternative, effective, safe drug which can decrease the morbidity from this potentially blinding disease. Topical Mitomycin - C (MMC) has been used in the management of allergic conjunctivitis.[8],[9]

MMC inhibits cell proliferation and is non cell cycle specific.[10] It has been previously used in pterygium surgery[11] glaucoma filtration procedures[12] and in management of conjunctival squamous cell neoplasia.[13],[14],[15],[16]

On literature search (Medline) we found only one study from Turkey, which has temperate climate, showing use of topical MMC in management of recalcitrant VKC.[8] The purpose of this study was to evaluate the effect of 0.01% MMC eye drops in patients of Indian origin [India has mostly tropical climate], with severe VKC refractory to topical steroid and mast cell stabilizers.


  Materials and Methods Top


The study was undertaken at the Post Graduate Institute of Medical Education and Research, Chandigarh, India after approval from the institutional review board. Twenty-eight patients with a history of severe VKC who provided informed consent were included in the study. All cases had been previously treated with a variety of topical drops in the form of mast cell stabilizers, antihistamines, anti-inflammatory drugs and steroids for at least one year before enrollment and all were refractory to this mode of treatment. Patients with shield ulcer, epithelial defect, associated ocular or systemic diseases, those taking oral medicines were excluded from the study. All patients had a wash out period of one week in which they were advised not to instill any eye drop. Only commercially available saline was given to the patients to be instilled if needed. After this period, patients underwent a detailed ophthalmic examination with specific note being made of itching, tearing, photophobia, mucous discharge and foreign body sensation. Specific signs looked for on slit lamp biomicroscopic examination included conjunctival hyperemia, punctuate keratitis, trantas dots, limbal edema and papillae. The grading system followed for categorizing symptoms and signs of VKC, is shown in [Table - 1]. These were graded on a scale of 0-3 using the method described by Bleik et al .[17] Patients subjectively graded their symptoms and the questionnaire was completed by the masked examiner (AKJ) who recorded the signs [Table - 2] and [Table - 3].

Patients were assigned at random to placebo or treatment with topical 0.01% MMC three times a day for 2 weeks in both eyes. A prespecified randomization scheme was followed in which patients seen on Tuesday and Friday were assigned to placebo group and those seen on Monday and Thursday received MMC drops. By using this randomization technique, 17 patients were assigned to MMC group and 11 cases to placebo group. Coding was done wherein patients in the MMC group were assigned code 1 and those in placebo group as code 2. The examiner was masked to this code which was revealed only at the end of the study. MMC was prepared by dissolving commercially available injectable MMC (2 mg vial, MitOnco, Neon Antibiotics Private Ltd, Thane, India) in 20 ml sterile distilled water without adding preservative. The pH of the resulting solution was kept at 6.2. Patients in the placebo group received only distilled water. Both MMC and placebo eye drops were dispensed in identical multodose plastic bottles and appearance of the medication was same in both as clear fluid. To ensure activity of MMC, fresh solution was prepared every third day. All cases remained masked to treatment till the end of trial. Signs and symptoms were recorded at the end of 1 and 2 week of the two week treatment period by a single, masked examiner (AKJ).

At the end of two weeks patients were given saline drops and were observed for another 4 weeks to monitor the course of the disease and to observe for any complications. Retreatment with topical steroids and mast cell stabilizers was started either on patients request as a result of severe symptoms or if one 3 + sign was observed by the examiner excluding the preexisting tarsal giant papillae in the observation period of 4 weeks. Also any difference between the requirement for medication in both the groups was noted.

Mann Whiteny test was used to compare the change in the severity of symptoms and signs from baseline to the two week follow-up of treatment period in the MMC and placebo group. A level of P 0.01 was taken as statistically significant. Patient reports of symptoms of VKC were not eye specific, therefore individuals were considered the unit of analysis for comparison of symptoms. However, the signs of VKC were graded separately for each eye. Wilcoxan test was used to calculate the significant value between the two groups in terms of improvement after 2 weeks. The Fisher exact test was used to compare the cases in the two groups who required medication during the one month post treatment follow up.


  Results Top


Twenty eight patients met the criteria for inclusion in this clinical trial. There were twenty four males and four females. Mean patient age was 12.29 years (range 6-22 years). Patients in the MMC group did not differ much in age from the placebo group (Mean age 12.94 vs 11.64). There was no statistically significant difference between the two groups in terms of severity of symptoms at presentation except for photophobia which was severe in the placebo group.( P =0.003).Signs of the disease did not differ significantly at presentation. Only punctate keratitis was significantly severe in the placebo group at presentation. ( P =0.01).

At the end of the two week treatment period patients assigned to the MMC group showed greater improvement in symptoms and signs of VKC compared with the placebo group [Table - 4]. Significantly greater improvement was observed for tearing ( P =0.001), foreign body sensation ( P =0.004), discharge ( P =0.001), hyperemia ( P <0.001), punctate keratitis ( P <0.001), limbal edema ( P <0.001) and trantas spots ( P <0.001).

No adverse effects of treatment with MMC were noted. Only 2 cases had punctate keratitis which disappeared after the drug was stopped. During the 4 week post treatment follow up none of the 17 patients in the MMC group required medicine for VKC. Nine out of eleven cases in the placebo group required mast cell stabilizers or steroids or both within one week of commencement of the observation period. ( P <0.001)


  Discussion Top


The present trial suggests that MMC is beneficial in severe VKC. The improvement noted was greater than in the placebo group. Statistically significant differences were observed for tearing, foreign body sensation, discharge, hyperemia, punctate keratitis, limbal edema and trantas spots. The results of present study were not very much different from earlier study.[8]

VKC is a poorly understood allergic disorder commonly seen in the young males. In arid climates there is an increased incidence of the limbal form of the disease. Additionally in these countries VKC has a more perennial nature and less tendency to regress.[18],[19] Corneal changes in VKC are considered to gauge the severity of the disease.[20] In temperate climate 20% patients have severe disease.[21] Untreated corneal complications as well as prolonged treatment with steroids lead to permanent impairment of vision. As the disease is self limiting, management is aimed at preventing these complications.

VKC is considered primarily an IgE mediated disease,[22] but IgG response is also seen.Th-2 like helper cells present in the conjunctiva of patients with VKC produce cytokines and chemokines that account for most of the pathophysiological aspects of allergic disorders including production of immunoglobulin E antibodies, recruitment or activation of mast cell, basophils, eosinophils, mucus hypersecretion, subepithelial fibrosis and tissue remodeling.[23] The active participation of various inflammatory cells in VKC related conjunctival inflammation along with their mediators and adhesion molecules result in ocular surface inflammation.

Management of VKC in tropical countries like ours is not easy because of the safety and cost as well as the easy availability of over the counter medicines. Mast cell stabilizers have not shown good results from Middle east and Africa.[24],[25] Topical steroids are effective but unsupervised treatment leads to unsuspected steroid induced glaucoma and cataract.[26],[27],[28] Bonini et al observed an incidence of 2% steroid induced glaucoma.[29] Cyclosporine 2% is not a good alternative as 60% patients relapse soon after treatment is stopped.[17] Antihistamines, mucolytics and non steroidal anti inflammatory drugs have not gained much importance. Other modalities of treatment such as cryotherapy, Beta radiation have been used with limited success .[20],[30],[31],[32]

MMC selectively inhibits DNA synthesis and is non cell cycle specific. At high concentration cellular RNA and protein synthesis is also suppressed. Rapidly dividing cells are the most sensitive. MMC 0.04% has been successfully used in conjunctival and corneal intraepithelial neoplasia.[14],[15],[16] Encouraging results have been seen in atopic keratoconjunctivitis by Akova et al .[33] Sodhi et al in his study showed topical MMC to be more effective than topical azelastine in the treatment of allergic conjunctivitis both in terms of relief of symptoms and resolution of signs.[9] The use of topical MMC in low doses did not cause any significant adverse effect in this study.[9] Tanaka et al reported significant improvement in ocular condition where intra-operative MMC was used after excision of papillae.[34] No adverse effect was seen in any of his patients. Topical MMC has been reported to be safe at low doses.[11],[35],[36] Frucht-Pery and Iksan did not observe any significant side effects with 0.01% MMC topical drops after pterygium surgery.[11] In none of these studies any adverse systemic side effect was noted. Intravesical instillation of MMC for bladder cancer did not result in systemic toxicity.[37] In present study no ocular or systemic side effects were observed. Akpek et al observed punctate keratitis in 2 patients treated with MMC .[8] Previous studies have also reported this side effect .[14],[15],[16] MMC has previously been demonstrated to delay wound healing by inhibiting cell proliferation.[38]

Newer mast cell stabilizers like lodoxamide and nedocromial sodium have shown to be better than sodium cromoglycate for treatment of VKC but these are at present not available in our country.[39],[40] Corticosteroids are potent anti-inflammatory agents. They can modulate human T-lymphocyte response. Gene expression and protein secretion of Th-2 and Th-1 clones are down regulated in a concentration dependent manner by corticosteroids.[41] Successful treatment of severe VKC can be achieved with control of ocular inflammation with steroids. However, long term use of topical steroids in severe VKC particularly in such a young age group is not desirable. Supratarsal injection of steroid has been used with success in severe cases of VKC.[42] However this is an invasive procedure and there is a risk of developing glaucoma or/and cataract. Moreover this procedure has to be carried out under general anesthesia in most of the cases depending on the age of the child. Also it is difficult to monitor the intraocular pressure in young children. Steroids are easily available over the counter in India and it is possible that unsupervised use may lead to complications.

MMC is a non selective inhibitor of cell migration and proliferation. We used topical MMC in VKC for its non-specific inhibitory effect on the migration and proliferation of inflammatory cells and fibroblasts causing the symptoms and signs and eventual tissue remodeling associated with VKC. None of our cases had shield ulcer or an epithelial defect. We do not recommend use of MMC in such cases as it can aggravate the problem. Although mast cell stabilizers, steroids are the first line therapy of severe VKC we recommend use of topical MMC 0.01% in recalcitrant and severe cases of VKC not responding to other drugs rather than increasing the dose and strength of topical steroids. Side effects are minimal and there is marked improvement in the signs and symptoms of VKC. Once the acute phase of severity of symptoms and signs of the disease is controlled by use of topical MMC, patients can be switched to mast cell stabilizers for maintenance.

 
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    Tables

  [Table - 1], [Table - 2], [Table - 3], [Table - 4]


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