Medroxyprogesterone to treat corneal thinning postcurvularia keratitis.

Keratitis of varied etiology is not uncommon in the Indian subcontinent. This case is one such an instance of keratitis caused by dematiaceous fungus in an urban dweller not engaged in farming or any other soil/earth-related work. Although healing of the ulcer occurred in the usual course, thinning persisted for a fortnight. This case highlights medroxyprogesterone acetate used topically to achieve collagen synthesis, thereby affect repair of the thinned cornea. Copyright:

Introduction

Fungal infections of the eye are a growing threat that have substantial morbidity and cost.[1] Aspergillus and Fusarium are recognized since long as ocular pathogens. However, isolation of dematiaceous fungi from a corneal ulcer is a rare entity amounting to <2%.[2] Although slow in progression, Curvularia species causes pigmentary or nonpigmentary keratitis with gradual focal suppuration leading to corneal thinning.[2] Among various treatment modalities described in literature, this case report highlights the role of medroxyprogesterone (MPG) 1% used topically for treating corneal thinning post healed infectious keratitis.

Case Report

A 44-year-old male presented to us with a history of trauma in the right eye by an organic foreign body following which he developed pain and redness. Except for hypertension, there was no systemic illness. At presentation, his visual acuity was 20/40 (6/12) and 20/20 (6/6) in the right and left eyes, respectively. Slit-lamp examination revealed circumcorneal congestion, with an ulcer in the inferotemporal aspect of the cornea extending up to the limbus. The margins were ill-defined, with irregular and dry surface and no pigmentary changes [Figure 1].

Figure 1

The ulceration under diffuse illumination on the first visit showing no pigmentary changes

Under all aseptic precautions, corneal scraping was obtained using the blade of Bard-Parker No. 15 knife, and potassium hydroxide mount was prepared, which showed septate fungal hyphae with occasional sporangia. The patient was instituted an empirical regimen of acetazolamide 250 mg BID orally along with topical natamycin 5%, moxifloxacin 0.5%, and homatropine 0.5%. A definitive diagnosis of curvularia fungal keratitis was made 10 days postincubation on the basis of growth obtained on Sabouraud dextrose agar [Figure 2].

Figure 2

(a) Microscopic × 40 view of growth inoculated in Sabouraud dextrose agar. (b) The growth seen in lactophenol cotton blue (×40). (c) Colony seen as gross in Sabouraud dextrose agar

Viewing this culture report, it was decided to add tablet fluconazole 150 mg BID orally to the treatment being administered and keep the patient on biweekly follow-up. On subsequent review done at the end of 2 weeks, the ulcer showed signs of healing [Figure 3]. However, due to stromal thinning, a facet was noted at the center of ulcer [Figure 4b]. With the objective of promoting stromal repair by inhibiting matrix metalloproteinases, oral doxycycline 100 mg BID was started and the patient was reviewed after a period of 10 days. Despite complete healing of keratitis [Figure 4a], due to the persistence of central stromal thinning, it was now that topical MPG 1% was considered in order to promote stromal repair. The prerequisite for the institution of this drug was to ensure complete epithelial healing which was done using fluorescein 2% stain. There was no epithelial defect. The rationale for using topical MPG was 3 fold. First, The efficacy of antifungal agent appears to be unaffected when used in conjunction with topical steroid.[3] Second, in a series of fungal keratitis, 15% of patients (19 out of 125) received topical steroid (for an average 24 days) for decreasing inflammation, and scarring showed faster signs of healing when this therapy was commenced after completing 2-week regimen of antifungal therapy; another animal study model of candida keratitis suggests that topical steroids after infective keratitis may be beneficial.[4] Finally, oral doxycycline already given in a dose of 500 mg bidaily for 2 weeks in this case being treated for curvularia keratitis could not produce appreciable and desired effect.

Figure 3

Healing keratitis postantifungal therapy

Figure 4

(a) Healed keratitis on diffuse illumination (b) with nebular opacity and central facet due to thinning on slit beam. (c) Improvement in the depth of facet postmedroxy progesterone treatment

Once MPG was started in a dose of 1% twice a day, it was continued for a week; thereafter, dosing was reduced to once a day for next week and withdrawn. Only lubricant was instilled now with the rationale that nature will take its course for further reparative process. Despite waiting for 2 weeks, substantial improvement in stromal thickness did not occur; therefore, MPG was commenced further for 2 weeks. At the end of two pulse doses, significant stabilization in corneal thinning was noted [Figure 4c].

Discussion

Medroxyprogesterone acetate (Depo-Provera) is a hormonal medication of the progestin type which is a 17-α hydroxyprogesterone derivative.[5] In addition to binding to the progesterone receptors, it also has an affinity for glucocorticoid receptors, thereby exerting its anti-inflammatory property.[5] As a part of cellular events in corneal ulceration, collagenase release is both PMN (polymorphonuclear cells) dependent (majority) as well as PMN independent. MPG inhibits the PMN-dependent collagenase, thus promoting collagen synthesis for repair.[5] MPG 1% is commercially not available as eye drops, however it can be reconstituted with injection[6] under aseptic conditions by diluting 1 ml of MPG to 15 ml with normal saline. 1 ml of the suspension was introduced into 15 ml sterile plastic eye drop bottle.[7].

Since progestational steroid such as medroxyprogesterone acetate (Provera, Pfizer) has a potentially important differential pharmacological effect that of reducing inflammation with lesser concomitant suppression of wound repair than corticosteroid, it can be used systemically, subconjunctivally, or topically in cases of burns and chemical injuries sustained by the cornea[8] and so can be substituted for corticosteroids at 10–14 days in such cases. Furthermore, medroxyprogesterone acetate 1% has been experimentally shown to suppress corneal neovascularization postburn cases and promote healing.[6] Doxycycline acts by inhibiting collagenolysis by inhibiting matrix metalloproteinase. Topical agents to reduce collagenolysis which are often used include 1% acetylcysteine and 1% MPG eye drops by virtue of being collagenase inhibitors or inhibitors of collagenase synthetase.

Ascorbic acid to enhance collagen synthesis and facilitate the process of stromal repair has the same effect.

This drug has successfully been used in corneal melt cases also, as it may have a protective effect with regard to melt onset and severity.[7] In a patient having Boston keratoprosthesis implanted,[7] MPG was used topically for a period of 4 weeks. Visante optical coherence tomography at 3 and 6 months after the treatment documented not only stabilization of corneal thinning but also slight thickening.[7]

Owing to its anti-inflammatory and collagenase inhibiting property, we used MPG 1% in corneal thinning postinfectious keratitis, which, as per the literature, the review has been used only in noninfectious cases. MPG 1% was started only after confirming epithelialization, and no flaring up of infection was noted in subsequent reviews.

Other alternatives for corneal repair are collagen cross-linking or amniotic membrane graft, both of which were not available.

Conclusion

Medroxyprogesterone acetate (Depo-Provera) can be considered in cases of corneal thinning secondary to infective keratitis, providing that the infection is well under control and epithelialization has occurred in order to achieve wound stabilization.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.