Indian Journal of Ophthalmology

CURRENT OPHTHALMOLOGY
Year
: 1993  |  Volume : 41  |  Issue : 1  |  Page : 3--14

Changing patterns of infectious keratitis : Overview of clinical and histopathologic features of keratitis due to acanthamoeba or atypical mycobacteria, and of infectious crystalline keratopathy


Stanislaus Kinota1, Kai W Wong2, Jyotirmay Biswas3, Narsing A Rao1,  
1 Eye Pathology Laboratory, Doheny Eye Institute, and the Departments of Ophthalmology, University of Southern California, USA
2 Eye Pathology Laboratory, Doheny Eye Institute, and the Departments of Ophthalmology, University of Southern California, and White Memorial Medical Center, Los Angeles, USA
3 Medical Research Foundation, Madras, India

Correspondence Address:
Narsing A Rao
Doheny Eye Institute, 1335 San Pablo Street, Los Angeles, CA 90033.
USA

Abstract

Acanthamoeba keratitis, infectious crystalline keratopathy and atypical mycobacterial keratitis have recently emerged as important types of infectious keratitis. These corneal infections have been associated with contact lens wear and with corneal surgical procedures such as radial keratotomy and penetrating keratoplasty, and the clinical setting of each of these infections is important in alerting the clinician to the possible diagnosis. There have been improvements in rapid diagnostic techniques for such infections in the last several years. Treatment has also improved, but remains a difficult problem, especially for Acanthamoeba. An overview of recent developments in the clinical and histopathologic methods for diagnosis and treatment options of these three corneal infections is provided.



How to cite this article:
Kinota S, Wong KW, Biswas J, Rao NA. Changing patterns of infectious keratitis : Overview of clinical and histopathologic features of keratitis due to acanthamoeba or atypical mycobacteria, and of infectious crystalline keratopathy.Indian J Ophthalmol 1993;41:3-14


How to cite this URL:
Kinota S, Wong KW, Biswas J, Rao NA. Changing patterns of infectious keratitis : Overview of clinical and histopathologic features of keratitis due to acanthamoeba or atypical mycobacteria, and of infectious crystalline keratopathy. Indian J Ophthalmol [serial online] 1993 [cited 2020 Feb 24 ];41:3-14
Available from: http://www.ijo.in/text.asp?1993/41/1/3/25626


Full Text

In recent years several unusual types of corneal infections have been diagnosed with increasing frequency: the diagnoses have been confirmed and the etiologic agents characterized by microbiological and histopathological methods. These infections include infectious crystalline keratopathy and keratitis due to atypical mycobacteria and Acanthamoeba. These infections have been reported to occur primarily following surgical procedures such as radial keratotomy [1] or penetrating keratoplasty [2],[3],[4],[5],[6],[7],[8] or in patients who wear contact lenses [9],[10],[11],[12], sub Several excellent reviews are available on the clinical signs and symptoms, routine histopathologic changes. and treatment of these relatively rare corneal infections [13],[14],[15],[16],[17],[18] Herein we present an overview of recent developments in the diagnosis and treatment of these three infectious corneal diaseases, with emphasis on pathologic changes.

 II. Acanthamoeba Keratitis



a. General considerations

Acanthamoeba keratitis is an uncommon corneal infection, although in recent years it is being seen with increased frequency, especially in contact lens wearers. This corneal infection is not endemic to any particular region, and cases have been reported from various parts of the world, including Europe, Asia and North and South America. The infection can become manifest in many different ways, including pain that is disproportionately severe to the ocular findings. A ring-shaped infiltrate [Figure 1]A surrounding a central stromal ulcer. which is characteristic of Acanthamoeba keratitis. may be seen at any time during the indolent course of the disease. [13],[19],[20],[21],[22] Management depends on early diagnosis and aggressive _ antimicrobial chemotherapy. [19].[23],[24],[25] However. despite longterm antimicrobial therapy, many patients ultimately require replacement of the diseased cornea by penetrating keratoplasty. [13],[15]

Acanthamoeba is a free-living ubiquitous protozoan found in air [26],[27] soil, [28],[29] and all types of water media, including salt water [30] and chlorinated water. [13],[31]sub It is unaffected by 0.85% concentration of sodium chloride solution [29] as well as by pH ranging from 3.9 to 9.75.[30] The organism can grow in culture at temperatures unto 42° C and can also remain viable at-20° C for three years .[22],[29] The life cycle of Acanthamoeba consists of active trophozoite and dormant cystic stages. [32] The adult trophozoite measures 16-47 microns in length, has a single nucleus and possesses fine, spine-like acanthopodia. [22],[28] The cyst also has a single nucleus, measures 10-25 microns in diameter and consists of a double wall with an outer ectocyst and an inner endocyst. [22],[33],[34] Pathogenic species that cause human diseases include A. castellani, A.polyphaga, A.culbertsoni and Hartmannella. [22],[35]

Since the first reported case of Acanthamoebic keratitis in 1973 by Jones. Robinson and Visvesvara (presented at the Ocular Microbiology and Immunology Group Meeting, Dallas, Texas, September, 1973) a few additional cases have been reported, usually in the form of single case reports or small series of cases. In a more recent report, a large number of cases were summarized by Stehr-Green et a1 [12] after surveying members of the Ocular Microbiology and Immunology Group and after reviewing specimen log books for laboratory requests for Acanthamoeba testing submitted to the Division of Parasitic Diseases of the Centers for Disease Control from January 1973 to July 1988. They identified 208 patients who were diagnosed as having Acanthamoeba keratitis. Of these patients, 101 (49%) were male and 107 (51 %) were female. The median age at onset of the keratitis was 29 years, with a range of 13-82 years. About 95% of the patients in this study had a history of corneal trauma, exposure to contaminated water or contact lens wear. In 138 of the patients, there was a history of contact lens wear: 56% wore soft daily-wear lenses, 19% wore soft extended-wear lenses, and 6% wore soft lenses of unspecified type; only 7% and 2% of these patients wore rigid gas-permeable or hard contact lenses, respectively. The remaining patients (8%) wore saturn lenses or other contact lenses. Of the 138 contact lens wearers, 88 had a history of using saline prepared with salt tablets and distilled water. [12]

b. Clinical manifestations

The clinical symptoms of Acanthamoeba keratitis include severe pain, blurred vision, photophobia, tearing and foreign body sensation. [13],[15],[18],[19] The infection typically has a protracted course with progressive worsening of the keratitis over several months. [13],[15],[19] However, deterioration can be rapid. [13] There are also reported cases with temporary remission. Clinical signs include decreased corneal sensation, conjunctival injection and chemosis with tarsal and limbal follicles. [13] Corneal changes consist offine epithelial and subepithelial opacities and epithelial microcystic edema [13],[36],[37] In two reported cases, a dendrite-like epitheliopathy was noted initially. [9],[38] The stroma usually shows a disciform infiltrate that is most dense at its periphery, resulting in an annular appearance that may be either segmental or circumferential. [13] In some advanced cases, however, the infiltrates are diffuse instead of annular, [9],[21],[39] and in other cases the infiltrate was noted along the corneal nerves. (Moore, McCulley and Kaufman, presented at the Ocular Microbiology and Infection Group Meeting, San Francisco, California, September, 1985). A nongranulomatous anterior chamber reaction is commonly present, [13] and increased intraocular pressure and cataract formation have been reported. [13] However, posterior segment involvement in Acanthamoeba keratitis is extremely rare, as are cystoid macula edema [13] and nodular scleritis. [40] Nongranulomatous uveitis was noted seven days after the onset of symptoms in an ultimately fatal case of Acanthamoebic meningitis. [20]

c. Diagnosis and Pathology

Accurate diagnosis of Acanthamoeba keratitis can be established with the aid of direct examination of corneal scrapings [Figure 1]B or in some cases by corneal biopsy [Figure 2] utilizing various special stains. Samples of corneal scrapings should be touched, not smeared, on the slide, [39] and spray fixative may be better than air drying. [25] Wet mount is effective for observing the mobile trophozoites. [22],[24] Acanthamoeba can be stained with hematoxylin-eosin, [33]sub periodic acid-Schiff, [22] Giemsa, [39]sub Trichrome, [39]sub Heidenhain's iron hematoxylin-eosin, [39] Gomori-methenamine-silver, [22] Wilder's reticulum, [13] Bauer chromic acid[ 13] and indirect fluorescence antibody staining 38 Wilhelmus et al [41]showed that staining of the parasite with calcofluor white with a counterstain of Evans blue can be simple, rapid and reliable.

Other rapid staining procedures for Acanthamoeba include fluorescein conjugated lectins such as concavalin-A, which is known to bind to the cell wall of the cysts; such cysts can then be easily detected with the aid of a fluorescence microscope [17] However, calcofluor white and the various lectins are nonspecific stains that also stain fungi and other organisms. In contrast, antibody histochemical or fluorescence stains provide specific staining that indicates not only the presence of Acanthamoeba, but also specific species of this protozoan. Moreover, these immunological methods can demonstrate vividly both cysts and trophozoites; the latter are not as easily identified with hematoxylin-eosin, calcofluor white or lectin binding methods.

Culture of the parasites on blood or chocolate agar is not as effective as using minimal nutrient agar with an Escherichia coli overlay, as the minimal nutrient agar minimizes growth of toxic competitive bacteria and the E.coli overlay provides a food source for the parasites [34] After incubation of the minimal nutrient agar with E.coli overlay at 37°C for 24 hours, clear plaques develop on the E.coli overlay; these plaques resemble those of cytopathic effect caused by virus in tissue culture, [22],[28],[34] and represent areas of E.coli consumed by the amoebae.

Histopathologic studies in actue infection may show, an infiltrate of polymorphonuclear leukocytes in various stages of degeneration, and stromal necrosis. [13],[15].[18] The overlying epithelium is usually absent or necrotic, and adjacent Bowman's layer is disrupted. Cysts and trophozoites are found within the areas of inflammation and necrosis. [17],[19],[23],[25],[39] In several reports, trophozoites, as well as cysts, were found in the stroma at sites that were free of inflammatory cell infiltration. [13],[15],[18] Morphologically, the cysts are easily identified by hematoxylin­eosin and other special stains such as periodic acid-Schiff, calcofluor white and lectins. The trophozoites exhibit prominent nuclei and basophilic intracellular organelles. Some trophozoites appear similar to reactive histiocytes or keratocytes, [19],[39] but these latter reactive cells can be easily differentiated from trophozoites with the aid of immunohistochemical methods.

There were ten cases of Acanthamoeba Keratitis [Table 1] logged into the pathology files at the Doheny Eye Institute from January 1985 through June 1989. In each of these cases the diagnosis was established by hematoxylin-eosin preparations. Special studies, such as calcofluor white stain, use of fluorescein conjugated lectins and immunohistochemical studies [Figure 3]A.B,C & D, were performed on several cases and confirmed the presence of encysted Acanthamoeba;staining of trophozoites was achieved with the peroxidase method [Figure 3]D. All these special procedures resulted in intense staining of the cytoplasmic membrane of the organisms rather than of the cyst wall [Figure 3]C.

Based on immunofluoescence and immunohistochemical stains, it appears that the cell membrane of the organisms is shared antigenically by the trophozoites and by the cysts, and that this membrane possesses potent antigenic determinants.

At the site of inflammatory cell infiltration, the cysts of Acanthamoeha show varying stages of degeneration [Figure 4]A. In contrast, organisms in the corneal stroma, where inflammatory cell infiltrations are absent, show well-preserved morphology with a distinct cyst wall and basophilic internal structures [Figure 4]B & C. Ultrastructurally. the cysts have a distinct electron dense outer ectocyst wall and an inner endocyst wall. The encysted organisms show a delicate cytoplasmic cell membrane [Figure 5]A.

These cysts of Acanthamoeba contain a large nucleus and a prominant nucleolus [Figure 5]B. Intracellularly the organism contains abundant rough surfaced endoplasmic reticulum and lipid vacuoles. In some cases, the keratitis caused by Acanthamoeba takes on a granulomatous character with giant and epithelioid cells. The ring infiltrates are thought to be due to activation of the complement-mediated pathway of complement or, alternatively, to antibody/antigen complex-inducing chemotaxis of polymorphonuclear leukocytes, which subsequently assume a ring formation. [13],[36]

sub The severity of the inflammatory cell infiltration varied markedly in the different corneal buttons that were removed during penetrating keratoplasty, with the buttons showing various degrees of corneal epithelial defects, disruption of Bowman's membrane, and strorrial necrosis [Table 1]. The stroma was infiltrated predominantly by polymorphonuclear leukocytes; these sites of inflammation in many instances contained necrotic cysts of Acantharnoeba. Morphologically, well-preserved cysts and occasional trophozoites were seen in areas of the stroma that were free from inflammatory cell infiltration. Even though we studied a limited number of cases for species indentification, it appeared that the stromal inflammation and necrosis were mild in infections produced by A.polyphaga, as compared with the severe keratitis produced by A.castellani [Table 1].

d. Treatment

In the treatment of Acanthamoeba Keratitis, a number of anti-amebic agents have been tried. In vitro sensitivity studies have shown that propamidine, dibromopropamidine, hydroxystilbamidine, clotrimazole, paromomycin and 5-fluorocystine are effective against Acanthamoeba. [42] The antifungal agents amphotericin B and candicidin also have some anti-amebic effects in vitro, as do some disinfectants, such as proflavine, acriflavine, and quinacrine, that are either too toxic or have no proven clinical benefit. Because of the small number of patients treated medically, without surgical intervention, it is difficult to assess the clinical effectiveness of these anti-amebic agents. [13] Resistance to 5-fluorocytosine, clotrimazole and chloramphenicol has been documented. [43] A combination topical therapy consisting of propamidine isethionate, neomycin, polymixin B and gramicidin was recently used in an unpublished multicenter study, based on earlier reports in vitro anti-amebic activity and some clinical response. Patients who were enrolled in this multicenter study are currently being followed to evaluate efficacy and toxicity.

A number of studies have shown that Acanthamoeba requires a coexisting bacterial or viral infection to become established, perhaps because the coexisting infection weakens the host immune mechanism as well as provides a food source for the organisms. [11],[12],[15],[18] Thus, in reported cases in which antiviral or antibacterial agents were used concomitantly with anti-amebic therapy, the results were better.

Corticosteroid use in Acanthamoeba infection can derease cellular damage due to inflammatory response; this promotes cyst formation and that inactivates the parasite. [20] However, corticosteroids can also worsen the infection by inducing host immunosuppression. Clinically, both beneficial and detrimental effects of corticosteroids have been demonstrated, and the results have been equivocal. The role of penetrating keratoplasty, as well as the timing for the initial surgery, is controversial. Penetrating keratoplasty appears to be more successful if performed before extensive corneal dissemination of the organisms, as a localised infection can be more easily removed through surgery. [13} Once there is extensive involvement, it is better to treat with intensive, longterm medical therapy in order to eliminate the parasites, after which surgical intervention can produce a satisfactory outcome.

 III. Infectious Crystalline Keratopathy



Infectious crystalline keratopathy is a recently recognized indolent bacterial infection that, in most reported cases, has occurred after penetrating keratoplasty. [2],[3],[4],[5][6],[7],[16] This This infectious process is characterized by branching infiltrates within the anterior stroma that simulate a mycotic infection. Gorovoy et al [4] reported a case of crystalline keratopathy in a corneal graft in 1983. Meisler et al [5] reported two patients who developed stromal crystalline keratopathy after penetrating keratoplasty, and another patient with herpes simplex keratitis who subsequently developed infectious crystalline deposits in the cornea, James et a1 [44]also reported a patient who developed a crystalline keratoplasty approximately 10 months after penetrating keratoplasty, and Reiss et al [6]sub reported a patient who developed crystalline keratopathy five months after penetrating keratoplasty. These cases and others are summarized in [Table 2].

The onset of clinical signs and symptoms of infectious crystalline keratopathy typically occurs several months after penetrating keratoplasty. [16] The delayed onset ranged from 3 to 36 months in the reported cases .[2],[3],[4],[5],[6],[7],[16],[44] was also reported as a co-infection in three cases of primary herpetic keratitis, [3],[7] and in two cases of Acanthamoebic keratitis. [45] Review of the pathology files of Doheny Eye Institute revealed three patients who were diagnosed as having infectious crystalline keratopathy, two following penetrating keratoplasty (one of the cases was previously reported) and one with ulcerative keratitis. [2] These three patients, and all other reported patients, were on steroid therapy along with various antimicrobial agents when the keratopathy developed.

The clinical symptoms of infectious crystalline keratopathy range from mild discomfort to pain, redness, severe photophobia and lid as well as conjunctival swelling [2],[3][4][5],[6],[7],[16] Clinical examination usually reveals conjunctival injection and chemosis. Corneal changes characteristically include anterior stromal infiltrate [Figure 6] with branching and crystalline opacities extending peripherally to the graft margin.[2],]3[,]4[,]5],[6],[7],[16],[44] There may also be associated epitheliopathy. The anterior chamber is usually quiet with rare cells; hypopyon, however, has been reported. [5]

Conjunctival swabs were nonproductive for culture and for cytology. Diagnostic keratectomy of the opacified area had a much higher yield for culture and cytology. Hispathologic examination of corneal buttons resected at penetrating keratoplasty or keratectomy typically showed aggregates of gram positive cocci in pockets between collagen lamellae of the superficial corneal stroma [Figure 7] beneath the Bowman's layer. In most instances there were no acute or chronic inflammatory cell accumulations near the bacteria. Electron microscopic examination confirmed the presence of cocci, characterized ultrastructurally by a laminated cell wall and plasma membrane, mesosomes, and ribosomes. [7] Bacteriological studies in most reported cases showed Streptococcus viridans to be the causative bacterial agents, with one case caused by Peptostreptococus; [3] two cases caused by Staphylococcus epidermidis; [16] and one case caused by both Strep. viridans and Staph. epidermidis. [16] Strep. viridans was revealed by culturing the corneal button or keratectomy specimen in two cases filed at the Doheny Eye Institute; the culture was nonrevealing in the remaining one case [Table 2]. In vitro susceptibility testing has shown that the streptococci are sensitive to penicillin, nafcillin, methicillin, cephalothin and vancomycin. [46]

The reported cases had been managed clinically, with longterm use of topical aminoglycosides with other broad spectrum antibacterial agents, including penicillin and methicillin. In severe cases, systemic methicillin and penicillin were also administered. The response to topical and systemic antibacterial agents was variable, and stromal scars invariably developed as sequelae. Eight of 18 reported cases eventually underwent repeated penetrating keratoplasty because of the severity of the infection and the poor response to medical therapy alone. [2],[3],[4],[5],[6],[7],]16],[44],[45] Of our three patients, two underwent repeat penetrating keratoplasty.

In summary, infectious crystalline keratopathy should be included in the differential diagnosis when a patient develops a superficial stromal crystalline keratitis that is indolent and refractory to steroid therapy, particularly if penetrating keratoplasty has been performed. The key to successful visual outcome in this infectious process is early diagnosis, by main­taining a high index of suspicion, and aggressive topical and/or systemic antibiotic therapy, with timely surgical debridement if needed.

 IV. Keratitis Due to Atypical Mycobacteria



Atypical mycobacteria, such as Mycobacterium fortuitum and Mycobacterium chelonei, are facultative pathogens that exist as saprophytes in the environment and may sporadically cause severe opportunistic infections in humans, including lung diseases, cutaneous abscesses, cellulitis and soft tissue infections, as well as postoperative wound infections, prosthetic valve endocarditis and others [47],[48] Reported ocular infections caused by atypical mycobacteria include keratitis, endophthalmitis, orbital granuloma, lacrimal drainage system infection and scleral abscess. [1],[8],[14],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65] The keratitis caused by these organisms has occurred in association with foreign body injury, contact lens wear, or after corneal surgical procedures, including penetrating keratoplasty, radial keratotomy, suture removal, and posterior capsulotomy, [49],[50],[51],[52],[53],[54],[55],[56],[59],[60],[62],[63],[64],[65]

M.fortuitum and M.chelonei belong to the Runyon's Group IV acid-fast bacilli that are non-spore forming, fast growing and pigment producing when exposed to light [59] They are distinguished from other rapidly growing mycobacteria by their arylsulfatase positivity. M.fortuitum differs from M.chelonei on the basis of positive iron uptake and nitrate reduction tests. [14] The atypical mycobacteria exist in soil and water and in the environment in a wide range of temperatures and humidities. [48] They also colonize body fluids, such as sputum and gastric contents, and skin surfaces of healthy individuals [49],[50],[51]

The exact mechanism of pathogenesis of mycobacterial infections is not well understood. Initial inoculation of the organisms appears to result from contaminated foreign bodies or surgical instruments. However, in only a few reported epidemic outbreaks of nonocular mycobacterial infections were the sources of contamination ever found [48] In ocular infections reported thus far, the search fo1 source of contamination was always futile. Following the initial inoculation of the organisms, infection of the cornea develops and the organisms gain access to the corneal stroma through disrupted epithelium and Bowman's layer. [1],[8],[14],[50],[52],[53],[54],[55],[60],[62],[63],[64][65], In one reported case of M.fortuitum keratitis of a contact lens wearer with no prior history of ocular trauma or surgery, the organisms may have gained access to the stroma through the epithelium that was compromised secondary to contact lens induced hypoxia or microtrauma. [14]

M.fortuitum keratitis is usually an indolent infection that lasts several months, with a waxing and waning clinical course. The most common initial symptoms are pain, redness and photophobia, followed by a decrease in vision [8],[14],[52],[53],[60],[62],[63],[64],[65]

An opaque corneal scar formed after resolution of the keratitis in most of the reported cases. [14],[52],[53],[60],[62],[63],[64],[65] In one case, enucleation was required after spontaneous perforation of the cornea. In another case, penetrating keratoplasty was performed because of rapid thinning of the cornea. [11]

The early signs of M.fortuitum keratitis can be subtle. A persistent epithelial keratopathy without stromal infiltrate or anterior chamber reaction may be the only presenting sign. White stromal plaques with radiating lines resembling a cracked windshield, described by Lazar et al, [52] may also be an early sign. As the disease progresses, large, whitish, dense stromal infil­trates develop. These large stromal infiltrates are multiple and are located in the anterior as well as deep stroma. The borders of the infiltrates are nondiscrete, similar to those observed in fungal keratitis and in stromal herpes simplex keratitis. Hypopyon is associated with the infection during exacerbation. [14]

Modified Ziehl-Neelsen stain is a sensitive and specific stain for alcohol resistant acid-fast bacilli such as M.fortuitum and M.chelonei. Sections of corneal biopsy stained with auramine 0 and examined by fluorescence miscroscopy will also demon­strate the location of the bacteria. Similarly, fluorescein conju­gated lectins are known to stain these bacteria. There are nucleic acid probes available for rapid specific diagnosis of these organ­isms by DNA hybridization techniques [66] If atypical mycobacteria are suspected, corneal scrapings or biopsy samples should be cultured on specific Lowenstein-Jensen media at 37°C or at room temperature.

Histopathologically, studies of M.fortuitumkeratitis showed ulceration of the epithelium and stroma. [14],[52],[53],[63],[64],[65] Multiple areas of stromal necrosis with acute and chronic inflammatory infiltrates were present. Numerous acid-fast organisms were observed within the stromal extracellular matrix as well as in macrophages and keratocytes. The stromal necrosis extended from the anterior surface to the deep layers. [52],[53],[63],[65]

The onset of clinical symptoms of M.chelonei keratitis is typically delayed. In reported cases, the onset of symptoms ranged from two weeks to three months after the trauma. [1],[50],[54],[55],[56]The clinical symptoms of reported cases of M.chelonei keratitis include foreign body sensation and irritation early in the course, with progression to pain and photophobia. The course of the infection is smoldering, despite antimicrobial therapy. Clinical signs upon presentation include epithelial defects along surgical incision wounds or suture tracts, and overlying white, irregular stromal infiltrates with radiating projections and fluffy indistinct margins [1],[50],[54],[55] The infiltrates are located at all levels of the stroma but tend to be concentrated in the mid-to-deep layers. A mild to moderate inflammatory reaction in the anterior chamber, without hypopyon, seems to be a common feature.

Similar to M.fortuitum, M.chelonei stains as gram-positive rods, and modified Ziehl-Neelsen stains identify the organisms as acid-fast bacilli. Lowenstein-Jensen media at 37°C or at room temperature provides specific growth medium for the identifica­tion of organisms. Histopathologic studies of M.chelonei keratitis revealed focal epithelial defects and stromal necrosis. [1],[50],[54],[55] Inflammatory cell infiltrates, along with occasional multinucleated giant cells, were noted. Numerous acid-fast organisms were demonstrated by modified Ziehl-Neelsen stain [Figure 8]. The organisms were located in the extracellular matrix as well as in the keratocytes of the stroma. Auramine 0 preparations showed myriad organisms within the stroma [Figure 9].

Both M.fortuitum and M.chelonei are usually resistant to conventional antituberculosis agents, including isoniazid. They are, however, susceptible, in vitro, to tetracycline, cefoxitin, doxycycline, erythromycin, aminoglycosides such as amikacin and tobramycin, as well as to sulfonamides. M. fortuitum is generally more sensitive to amikacin, doxycycline and sulfonamides than is M. chelonei. Dalovisio et [67],[68] successfully treated M. chelonei keratitis with amikacin, 10 mg/ ml topically. However, subsequent reports have documented treatment failure with amikacin applied topically at doses up to 5 times greater than those reported by Dalovisio et al [67],[68] The treatment failures may be due to inadequate penetration of the antimicrobial agents to the deep stroma, to delayed diagnosis, and/or to virulence of the organisms. There are also concerns that previous use of corticosteroids topically may contribute to the chronicity and to treatment failure in cases of M. fortuitum keratitis. Surgical debridement of diseased corneal tissue can also be an effective therapeutic choice, as the keratitis improved or resolved after keratotomy or penetrating keratoplasty.

 V. Conclusion



In conclusion, contact lens usage in the U.S., including daily and extended wear types for refractive as well as cosmetic purposes, has tripled over the past 10 years. Improvements in storage techniques for donor corneas, combined with expansion of indications for penetrating keratoplasty, have resulted in increased numbers of this procedure being performed; other corneal surgeries, such as radial keratotomy, lamellar keratoplasty, -and epikeratophakia are also being performed with increased frequency. As a result, the incidence of the unusual types of keratitis reviewed in this article can be expected to increase. Ophthalmologists should be aware of this changing pattern, and include these entities in the differential diagnosis of patients presenting with keratitis. Early recognition, prompt and accurate diagnosis by the many new, rapid diagnostic methods, and aggressive treatment may shorten the course and lessen the severity of these infectious diseases, thereby minimizing ocular morbidity.

ACKNOWLEDGEMENTS

This study was supported in part by a grant from Research to Prevent Blindness, Inc., New York, NY and by Core Grant 3040 from the National Institutes of Health, Bethesda, MD.

[Figure 1] was provided by Dr.David Schanz!in and [Figure 6] was provided by Dr.John Irvine. Dr.Mel Trousdale provided antibodies to Acanthamoeba. The authors are grateful for the technical assistance of Mr.David Stanforth and editorial assist­ance of Ms.Ann Dawson.

References

1Robin JB, Beatty RF, Dunn S, Trousdale MD, Riffenburgh R and Rao N. Mycobacterium chelonei keratitis after radial keratotomy. Am J Ophthalmol. 102: 72-79, 1986.
2Dunn S, Maguen E and Rao NA. Noninflammatory bacterial infiltration of a corneal graft. Cornea 4: 189-193,1986.
3Eiferman RA, Ogden LL and Snyder J. Anaerobic peptostreptococcal keratitis. Am J Ophthalmol. 100: 335-336, 1985.
4Gorovoy MS, Stern GA, Hood CL and Allen C. Intrastromal noninflammatory bacterial colonization of a corneal graft. Arch Ophthalmol. 101; 1749-1752, 1983.
5Meisler DM, Langston RHS, Naab TJ, Aaby AA, Mc Mohan JT and Tubbs RR. Infectious crystalline keratopathy. Am J Ophthalmol. 97: 337-343, 1984.
6Reiss GR, Campbell RJ and Bourne WM. Infectious crystalline keratopathy. Surv Ophthalmol. 31: 69-72, 1986.
7Samples JB, Baumgartner SD and Binder PS. Infectious crystalline keratopathy: an electron microscope analysis. Cornea 4: 118-126, 1985/1986.
8Wunsh SE, Boyle CL, Leopold IH and Littman ML. Mycobacterium fortuitum infection of corneal graft. Arch Ophthalmol. 82: 602-607, 1969.
9CDC. Acanthamoeba keratitis associated with contact lenses-United States. MMWR 35:405-408, 1986.
10John T,Desai D and SahmD.Adherence ofAcanthamoeba castellanii to new daily wear, extended wear, and disposable soft contact lenses. CLAO J. 17: 109-113, 1991.
11Moore MB, McCulley JP, Luckenbach M, Gelender H, Newton C, Mc Donald MB and Visvesvara GS. Acanthamoeba keratitis associated with soft contact lenses. Am J Ophthalmol. 100: 396-403, 1985.
12Stehr-Green JK, Bailey TM and Visvesvara GS. The epidemiology of acanthamoeba keratitis in the United States. Am J Opthalmol. 107: 331-336, 1989.
13Auran JD, Starr MB and Jakobiec FA. Acanthamoeba keratitis: review of the literature. Cornea 6: 2-26, 1987.
14Dugel PU, Holland GN, Brown HH, Petit TH, Hofbauer JD, Simons KB, Ullman H, Bath PE and Foos RY. Mycobacterium fortuitum keratitis. Am J Ophthalmol. 105: 661-669, 1988.
15Hirst LW, Green WR, Merz W, Kaufmann C, Visveswara GS, Jensen A and Howard M. Management of Acanthamoeba keratitis: case report and review of the literature. Ophthalmol­ogy 91: 1105-1111, 1984.
16RemeijerL, VanRij G, Mooij CM, Infectious crystalline keratopathy. Doe Ophthalmol. 67: 95-103, 1987.
17Robin JB, Chan R, Rao NA, Fluorescein-conjugated lectin visualization of fungi and acanthamoebae in infectious keratitis. Ophthalmology 96: 1198-1202, 1989.
18Watson PG. Amoebic infection of the eye. Trans Ophthalmol Soc UK. 95: 204-206, 1975.
19Cohen EJ, Buchanan HW, Langhrea PA, Adams CP, Galentine PG, Visveswara GS, Folberg R, Arentsen JJ and Laibson PR. Diagnosis and management of Acanthamoeba keratitis. Am J Ophthalmol. 100 : 389-395,1985.
20Jones DB, Visvesvara GS and Robinson NM: Acanthamoeba polyphaga keratitis and Acanthamoeba uveitis associated with fatal meningoencephalitis. Trans Ophthalmol Soc UK. 95: 221-232, 1975.
21Ma P, Willaert E, Juechter KB and Stevens AR. A case of keratitis due to Acanthamoeba in New York, New York, and features of 10 cases. J Infect Dis. 143: 662-667, 1981.
22Visvesvara GS. Free-living pathogenic amoebae. In Manual of Clinical Microbiology, 3rd ed. Lennette EH, Balows A, Hausler WJ Jr, Truant JP, eds. Washington, DC: American Society for Microbiology, 1980: 704-708.
23Hanssens M, DeJonckheere JF and DeMeunynck C. Acanthamoeba keratitis: a clinicopathological case report. Int Ophthalmol. 7: 203-213, 1985.
24McGill JL. Acanthamoeba: In Current Ocular Therapy 2, Fraunfelder FT, Roy FH, eds. Philadephia: WB Saunders, 64­65, 1985.
25Wright P, Warhurst D and Jones BR. Acanthamoeba keratitis successfully treated medically. Br J Ophthalmol. 69: 778-782, 1985.
26De Jonckheere JF. Ecology of Acanthamoeba. Rev Infect Dis. 13 (Suppl 5). S385-S387, 1991.
27Kingston D and Warhurst DC. Isolation of amoebae from the air. J Med Microbiol. 2: 27-36, 1969.
28Chang SH. Small, free-living amoebae: cultivation, quantitation, identification, classification, pathogenesis and resistances. Curr Top Comp Pathobiol. 1: 201-254, 1971.
29Culbertson CG. The pathogenicity of soil amoebae. Annu Rev Microbiol. 25: 231-254, 1971.
30Sawyer TK, Visvesvara GS and Harke BA. Pathogenic amoeba from brackish and ocean sediments, with a description of Acanthamoeba hatchetti, n. sp. Science 196: 1324-1325, 1977.
31Mergeryan H. The prevalence of Acanthamoeba in the human environment. Rev Infect Dis. 13(Suppl 5): S390-S391, 1991.
32Larkin DFP. Acanthamoeba keratitis. Int Ophthalmol Clin. 31(2): 163-172, 1991.
33Beaver PC, Jung RC and Cupp EW. Clinical Parasitology, 9th ed. Philadelphia: Lea & Febiger, 135-148, 1984.
34Visvesvara GS and Baslanuith W. Comparative studies on related free-living and pathogenic amoebae with special reference to acanthamoeba. J Protozool. 22: 245-256, 1975.
35Beattie AN, Slomovic AR, Rootman DS and Hunter WS. Acanthamoeba keratitis with two species of Acanthamoeba. Can J Ophthalmol. 25: 260-262, 1990.
36Lund OE, Stefani FH and Dechant W. Amoebic Keratitis: a clinicopathologic case report. Br J Ophthalmol. 62: 373-375, 1978.
37WarhurstDC, Stamm WP and Phillips EA. Acanthamoeba from a new case of corneal ulcer. Trans R Soc Trop Med Hyg. 70: 279, 1976.
38Epstein RJ, Wilson LA, Visvesvara GS and Plourde EG, Jr. Rapid diagnosis of Acanthamoeba keratitis from corneal scrapings using indirect fluorescent antibody staining. Arch Ophthalmol. 104: 1318-1321, 1986.
39Theodore FH, Jakobiec FA,Juechter KB, Pearl MA, Troutman RC, Pang PM and Iwa moto T. The diagnostic value of a ring infiltrate in Acanthamoebic keratitis. Ophthalmology 92: 1471-1479, 1985.
40Mannis MJ, Tamaru R, Roth AM, Acanthamoeba sclerokeratitis: determining diagnostic criteria. Arch Ophthalmol. 104: 1313-1317, 1986.
41Wilhelmus KR, Osato MS, Font RL, Rapid diagnosis of Acanthamoeba keratitis using calcofluor white. Arch Ophthalmol. 104: 1309-1312, 1986.
42Duma RJ and Finley R. In vitro susceptibility of pathogenic Naegleria and acanthamoeba species to a variety of therapeutic agents. Antimicrob Agents Chemother. 10: 370­376, 1976.
43Stevens AR and O'Dell WD: In vitro and in vivo activity of 5-fluorocytosine on acanthamoebe. Antimicrob Agents Chemother. 6: 282-289, 1974.
44James CB, McDonnell PJ and Falcon MG. Infectious crystalline keratopathy. Br J Ophthalmol. 72: 628-630, 1988.
45Davis RM, Schroeder RP, Rowsey JJ, Jensen HG and Tripathi RC. Acanthamoeba keratitis and infectious crystalline keratopathy. Arch Ophthalmol. 105: 1524-1527, 1987.
46Bourgault AM, Wilson WR and Washington JA II. Antimicrobial susceptibilities of species ofviridans streptococci. J Infect Dis. 140: 316-321, 1979.
47Beck F Pulmonary disease due to atypical tubercle bacilli. Am Rev Respir Dis. 80: 738-743, 1959.
48Wallace RJ Jr, Swenson JM, Silcox VA, Spectrum of disease due to rapidly growin mycobacteria. Rev Infect Dis. 5: 657-679, 1983.
49Edwards LB and Palmer CE. Isolation of "atypical" mycobacteria from healthy persons. Am Rev Respir Dis. 80: 747-749, 1959.
50Gangadharam PRJ, Lanier JD and Jones DE. Keratitis due to Mycobacterium chelonei. Tubercle 59: 55-60, 1978.
51Hand LW and Sandford JP. Mycobacterium fortuitum­A human pathogen. Ann Intern Med. 73: 971-977,1970.
52Lazar M, Nemet P, Bracha R and Campus A. Mycobacterium fortuitum keratitis. Am J Ophthalmol. 78: 530­532, 1974.
53LevensonDS and Harrison CH. Mycobacterium fortuitum corneal ulcer. Arch Ophthalmol. 75: 189-191, 1966.
54Meisler DM, Friedlaender MH and Okumoto M. Mycobacterium chelonei keratitis. Am J Ophthalmol. 94: 398­401, 1982.
55Mirate DJ, Hull DS, Steel JH Jr and Carter MJ. Mycobacterium chelonei keratitis: a case report. Br J Ophthalmol. 67: 324-326, 1983.
56Newman PE, Goodman RA, Waring GO III, Finton RJ, Wilson LA, Wright J and Cavanagh HD. A cluster of cases of Mycobacterium chelonei keratitis associated with outpatient office procedures. Am J Ophthalmol. 97: 344-348, 1984.
57Pope J Jr, Sternberg P Jr, McLane JN, Mycobacterium chelonae scleral abscess after removal of a scleral buckle. Am J Ophthalmol. 107: 557-558, 1989.
58Roussel TJ, Stem WH, Goodman DF and Whitcher JP Postoperative mycobacterial endophthalmitis. Am J Ophthalmol. 107: 403-406, 1989.
59Runyon EH. Anonymous mycobacteria in pulmonary disease. Med Clin North Amer. 43: 273-290, 1959.
60Sexton RR. Mycobacterium fortuitum infection of the cornea. In Corneal and External Diseases ofthe Eye, Polack FM, ed. Springfield: Charles C Thomas, 25-28, 1970.
61Smith RE, Salz JJ, Moors R, Silverstein D and Lewis W. Mycobacterium chelonei and orbital granuloma after tear duct probing. Am J Ophthalmol. 89: 139-141, 1980.
62Turner L. Atypical mycobacterial infections in ophthal­mology. Trans Amer Ophthalmol Soc. 68: 667-729, 1970.
63Turner L and Stinson I. Mycobacterium fortuitum as a cause of corneal ulcer. Am J Ophthalmol. 60: 329-331, 1965.
64Willis WE and Laibson PR. Intractable Mycobacterium fortuitum corneal ulcer in man. Am J Ophthalmol. 71: 500-504, 1971.
65Zimmerman LE, Turner L and McTigue JW. Mycobacterium fortuitum infection ofthe cornea: a report oftwo cases. Arch Ophthalmol. 82: 596-601, 1969.
66Rao NA. A laboratory approach to rapid diagnosis of ocular infections and prospects for the future. Am J Ophthalmol. 107: 283-291, 1989.
67Dalovisio JR and Pankey GA. In vitro susceptibility of Mycobacterium fortuitum and Mycobacterium chelonei to amikacin. J Infect Dis. 137:318-321, 1978.
68Dalovisio JR, Pankey GA, Wallace RJ and Jones DB. Clinical usefulness of amikacin and doxycycline in the treatment of infection due to Mycobacterium fortuitum and Mycobacteria chelonei. Rev Infect Dis. 3: 1068-1074, 1981.