Spontaneous Corneal Graft Ulcerative Perforation Due to Mixed Acanthamoeba and Herpes Simplex Keratitis: a Clinicopathologic Study

Home , Acanthamoeba keratitis, Herpes simplex keratitis

Spontaneous Corneal Graft Ulcerative Perforation Due to Mixed Acanthamoeba and Herpes Simplex Keratitis: A Clinicopathologic Study

Shimon Rumelt, M.D., Isaac Cohen, M.D., and Uri Rehany, M.D., F.A.C.S.

The clinical diagnosis of Acanthamoeba and herpes CASE REPORT keratitis is often challenging, because both share common clinical features (1–3). These include epithelial de- A 38-year-old patient underwent penetrating kerato- fects, punctate staining, epithelial haze, pseudodendrites, plasty for corneal scarring and thinning due to recurrent stromal edema, and stromal infiltrates. Melting and thin- herpes simplex keratitis. Six years after failing to follow ning of the corneal stroma are a frequent manifestation of up, he presented with spontaneous ulcerative perforation stromal herpetic disease but have also been described in of the corneal graft. Visual acuity at presentation was Acanthamoeba infection (3). Decreased corneal sensitiv- counting finger at 3 feet in the left perforated eye and ity is another common sign for both corneal infections 20/20 in the fellow eye. The perforated corneal graft was (4). Favorable response to antiviral medications has been replaced. Histologic examination of the perforated graft reported for Acanthamoeba keratitis, but the response is revealed stromal melting, with inflammatory response only temporary (1). Several unique features of Acanth- accentuating polymorphonuclear cells and lymphocytes. amoeba infection may ease the differentiation from her- No multinucleated epithelial cells suggesting viral infec- petic infection and include severe ocular pain and radial tion and no bacteria or parasites were identified in the keratoneuritis (5). pathologic specimens. Aerobic and anaerobic bacterial Because improper treatment of these infections may and viral cultures were negative. The patient was treated result in corneal necrosis and perforation or severe vas- with intravenous gentamicin sulfate, 80 mg t.i.d., cefa- cularized scarring, it is mandatory to determine the cor- zolin sodium, 1.0 g t.i.d., topical ciprofloxacin HCl, rect diagnosis rather early, although laboratory diagnosis 0.35%, prednisolone trimethylacetate, 0.5% q.i.d., and may frequently be difficult (6). atropine, 1% b.i.d. Visual acuity improved to 20/80, and Recently it was reported that keratitis may be caused the graft remained clear for 3 weeks when the patient had by mixed infection of Acanthamoeba and herpes simplex temporal marginal corneal graft ulcer accompanied by 3 (7). Mixed infections such as this are even more chal- superficial vascularization and anterior-chamber reac- lenging to diagnose, and if misdiagnosed may result in tion. The patient was again treated by the same antibiotic poor outcome. To our best knowledge, our report de- treatment, although bacterial cultures were negative. scribes, for the first time, the coexistence of Acantham- Two weeks later, an additional marginal ulcer appeared. oeba and herpes simplex in a corneal transplant, causing This ulcer that progressively deepened, resulting in spon- acute stromal melting and spontaneous corneal graft per- taneous perforation 6 weeks later (Fig. 1). The corneal foration. Such a devastating event emphasizes the im- graft was replaced, accompanied by extracapsular cata- portance of early diagnosis and treatment of mixed cor- ract extraction and implantation of posterior chamber neal graft infections. intraocular lens. The patient was treated again with topical ciprofloxacin HCl, 0.35% q.i.d., prednisolone trimethylacetate, 0.5% q.i.d., and parenteral fluocortolone, Submitted March 12, 1999. Revision received May 28, 1999. Ac- cepted June 1, 1999. 60 mg/day, tapered gradually over 6 weeks. A loading From the Departments of Ophthalmology (S.R., U.R.) and Pathology dose of oral cyclosporin A (600 mg/day) was initiated. (I.C.), Nahariya Medical Center, Nahariya, Israel. The dose was tapered gradually to maintain a blood level Address correspondence and reprint requests to Dr. Uri Rehany, Department of Ophthalmology, Nahariya Medical Center, P.O. Box 21, of 300–600 ng/ml. 22100 Nahariya, Israel. Histologic examination of the corneal button revealed

240 GRAFT PERFORATION DUE TO MIXED KERATITIS 241

B). The epithelial cells stained positively with peroxidase antiperoxidase (PAP) immunostain for herpes simplex virus polyclonal antibodies (Fig. 3). In areas of stromal infiltration, viable cysts of Acanthamoeba species mea- suring 10–15 ␮m in diameter were identified and stained positively with Gomori’s methenamine-silver and peri- odic acid–Schiff (PAS; Fig. 4).

DISCUSSION An accurate early diagnosis of Acanthamoeba and herpetic keratitis is the key for proper management, avoid- ing irreversible damage, and scarring or even perforation FIG. 1. A clinical photograph of the perforated corneal of the infected cornea or corneal graft. The diagnosis of graft. The stroma of the transplant is diffusely opacified these corneal infections is based mainly on clinical ob- because of edema and infiltrate. A perforation is noted at servations and rarely on laboratory tests, which are of the graft–host interface at 5 o’clock. low sensitivity and are rather expensive (6). In >50% of mixed infection with Acanthamoeba species and herpes the cases with Acanthamoeba keratitis, there is an initial simplex. The treatment was changed accordingly to sys- misdiagnosis of herpetic keratitis, because both microor- temic acyclovir, starting with 800 mg/day for the first 2 ganisms have similar clinical manifestations (1–3), and months and then tapered gradually over the following 6 further complicating this picture is that both agents have months, in conjunction with topical treatment with 3% been demonstrated coexisting in the same corneas (3,7). acyclovir ointment, q.i.d. Topical propamidine isethio- In some of these cases, Acanthamoeba is assumed to be nate, 1%, was instilled q.i.d. and tapered gradually over an incidental finding because it was detected by tandem the following 3 months. After 1 year of follow-up, the confocal microscopy in healthy corneas, whereas in other corrected visual acuity improved to 20/80, and the cor- cases, it caused an active disease. neal graft remained clear. Acanthamoeba keratitis may be superimposed on herpetic epithelial keratitis. Breakdown of the corneal epithelium due to herpetic infection may be a predisposing Histologic Examination factor for Acanthamoeba infection, allowing it to pen- The histologic specimen of the last perforated corneal etrate into the corneal stroma and proliferate. The epi- graft demonstrated multinucleated epithelial cells with thelial and stromal debris may serve as nutrients for the intranuclear eosinophilic inclusion bodies of Cowdry amoeba (8). type-A, surrounded by dense chromatin (Fig. 2A and Corneal transplants may be more prone to mixed in-

FIG.2.A: Histologic section through the perforated corneal graft. Multinucleated epithelial cells are found within the corneal epithelium (straight arrow). The Bowman’s layer is dis- rupted by inflammatory infiltrate of mononuclear cells and few polymorphonuclear cells (curved arrow). The infiltrate occupies the anterior stroma (H&E, original magnification ×200). B: Multiple giant multinucleated epithelial cells containing intranuclear eosinophilic inclusion bodies (arrow) surrounded by condensed chromatin (H&E, original magnification ×400).

Cornea, Vol. 19, No. 2, 2000 242 S. RUMELT ET AL.

It has been reported that patients with amoebic keratitis who were treated with topical corticosteroids may need penetrating keratoplasty in higher incidence than those who were not treated with these agents (10). The need for corneal transplantation due to amoebic keratitis was significantly increased when topical corticosteroids were administered (10). Thus, cautious use of corticosteroids is mandatory when corneal graft infection is suspected or when an atypical healing course is evident, as in our case. When bacterial cultures are negative, or no response to wide-spectrum antibiotics is apparent, other infectious agents should be suspected. If clinical and laboratory investigation confirms the diagnosis of herpes keratitis but antiviral treatment fails, a possible mixed infection FIG. 3. The epithelial cells stained positively with PAP should also be suspected. A proper scraping or biopsy immunostain for herpes simplex virus polyclonal antibodies (original magnification ×200). should be taken and examined by using special stains or polymerase chain reaction in addition to conventional microbiological cultures. In rare cases, when laboratory fections than intact healthy corneas because of the fre- work-up is indecisive or inaccessible for Acanthamoeba quent use of topical corticosteroids given to decrease the and/or herpes, an empiric combined treatment with an- immune response and graft rejection. The discontinuity tiviral and antiamoebic agents may be tried. Tandem of the corneal epithelium at the graft–host interface and confocal microscopy may also be of value in detection of the presence of the sutures may serve as a nidus for Acanthamoeba in cases initially diagnosed as bacterial or infections. Acanthamoeba is a ubiquitous microorganism herpetic keratitis. and is found in various liquid media including eyedrops Early treatment may improve the outcome for Acan- (9). Therefore it is likely that Acanthamoeba may be thamoeba and mixed infections and may prevent irre- found in the future more often in corneal grafts. versible damage due to severe stromal involvement re- quiring penetrating keratoplasty for visual rehabilitation (11,12).

REFERENCES 1. Auran JD, Starr MB, Jakobiec FA. Acanthamoeba keratitis: a review of the literature. Cornea 1987;6:2–26. 2. Bacon AS, Frazer DG, Filcker LA, et al. A review of 72 consecu- tive cases of Acanthamoeba keratitis, 1984-1992. Eye 1993;7:719– 25. 3. Mathers WD, Sutphin JE, Folberg R, et al. Outbreak of keratitis presumed to be caused by Acanthamoeba. Am J Ophthalmol 1996; 121:129–42. 4. Perry HD, Donnenfeld ED, Foulks GN, et al. Decreased corneal sensation as an initial feature of Acanthamoeba keratitis. Ophthal- mology 1996;102:1565–8. 5. Moore MB, McCulley JP, Newton C, et al. Radial perineuritis as a presenting sign in Acanthamoeba keratitis. Ophthalmology 1987; 94:1654–61. 6. Nesburn AB. Immunologic aspects of herpes simplex disease. In: Suran I, Gery I, Nussenblatt R, eds. Immunology of the eye, work- shop III: immunologic aspects of ocular disease. Bethesda, MD: National Eye Institute, 1981:21–42. 7. Mathers WD, Goldberg MA, Sutphin JE, et al. Coexistence of Acanthamoeba keratitis and herpetic keratitis. Arch Ophthalmol 1997;115:714–8. 8. Jones DB. Acanthamoeba: the ultimate opportunist? Am J Oph- thalmol 1986;102:527–30. 9. Warhurst DC. Pathogenic free living bacteria. Parasitol Today 1985;1:24–9. 10. Tay-Kearney ML, McGhee CN, Crawford GJ, Trown K. Acanth- amoeba keratitis: a masquerade of presentation in six cases. Aust N FIG. 4. Viable cysts of Acanthamoeba (arrows) measur- Z J Ophthalmol 1993;21:237–45. ing 10–15 µm are identified in areas of stromal infiltration 11. Bacon ASB, Dart JKG, Ficker LA, et al. Acanthamoeba keratitis: (PAS, original magnification ×200). the value of early diagnosis. Ophthalmology 1993;100:1238–43.

Cornea, Vol. 19, No. 2, 2000