CLINICAL SCIENCE

Penetrating Keratoplasty in Active Acanthamoeba Keratitis

Truc H. Nguyen, MD,* Robert W. Weisenthal, MD,* George J. Florakis, MD, James J. Reidy, MD, Ronald N. Gaster, MD, and Danita Tom, MD
Ficker et al8 reported 7 recurrences among 13 grafts in 7 eyes with uncontrolled infection. However, PK for AK can provide visual rehabilitation. Awwad et al11 reported a series of 13 patients who underwent PK after resolution of the keratitis with good results. We now report a series of 9 patients who underwent therapeutic PK in active AK, which produced clear grafts and good visual acuity without recurrences of infection. The indications for surgical intervention were deep stromal keratitis or peripheral corneal extension not responding to medical therapy or poor compliance with medical therapy producing progressive disease.

Purpose: To report the results of penetrating keratoplasty (PK) in

active Acanthamoeba keratitis (AK).

Methods: Nine patients with deep stromal inltrates because of AK were treated with intensive antiamoebic medical therapy followed by PK during the acute infectious phase because of poor clinical response or poor compliance. Antiamoebic therapy was tapered after PK. Results: Visual acuity ranged from 20/15 to 20/50 after an average
of 17 months after PK with no signs of recurrences. Patients had rapid resolution of symptoms.

Conclusion: PK is a viable option for active AK not responding to maximum medical treatment.
Key Words: Acanthamoeba keratitis, therapeutic penetrating keratoplasty (Cornea 2010;29:10001004)

MATERIALS AND METHODS

Nine patients underwent therapeutic PK for active AK from August 2004 to February 2007 in 4 separate institutions. Four patients were treated at Upstate Medical University, 1 patient was treated at the State University of New York at Buffalo, 2 patients were treated at the Columbia University Harkness Eye Institute, and 2 patients were treated at University of California, Irvine. All patients were referred without the diagnosis of Acanthamoeba for further evaluation and treatment after initial therapy elsewhere. Patient demographics and characteristics are listed in Table 1. There were 2 male and 7 female patients with ages ranging from 17 to 56 years. All patients were contact lens (CL) wearers; 1 patient had overnight CL use (patient 1), 2 patients had a history of swimming (patients 4 and 8), and 2 patients used tap water for CL maintenance (patients 6 and 9). Symptoms on presentation included pain, photophobia, and tearing. Duration of symptoms before the diagnosis of AK ranged from 2.5 weeks to 5 months (average 7 weeks). Initial corneal ndings included persistent epithelial defect, perineuritis, diffuse and deep stromal inltrate, and ring inltrate (Fig. 1). Five patients were initially treated for presumed herpes simplex keratitis, 2 patients were treated for bacterial keratitis, 1 patient was treated for herpes zoster, and 1 patient was treated for a corneal abrasion. Seven patients were on topical steroids before the diagnosis of AK. Acanthamoeba was presumptively diagnosed through clinical signs in all but 1 patient and conrmed by culture in 3 patients (patients 4, 5, and 9). One patient (patient 2) was diagnosed with a corneal scraping, and another patient (patient 3) had a corneal biopsy positive for Acanthamoeba. Confocal microscopy was used in 6 patients (patients 1, 2, 3, 4, 5, and 6) showing ndings consistent with Acanthamoeba. One patient (patient 7) was diagnosed by histopathology after urgent grafting. Histopathology of the excised tissue conrmed the diagnosis of Acanthamoeba in all patients in this series.
Cornea  Volume 29, Number 9, September 2010

canthamoeba keratitis (AK) is a potentially blinding infection whose incidence may be on the rise.1,2 The diagnosis and treatment of AK is challenging. The clinical presentation may vary and mimic other diseases, cultures may have limited yield, and more sensitive methods of diagnosis such as confocal microscopy3 and polymerase chain reaction are not widely available. Although current medical therapy has signicantly improved, particularly those medications with improved cysticidal activity, deep stromal cystic form of the protozoa can be difcult to eradicate because of poor corneal penetration.4 In addition, the prolonged course of treatment may produce corneal toxicity.5 Surgical management includes epithelial debridement in the early stages,6 deep lamellar keratectomy with conjunctival ap,7 and penetrating keratoplasty (PK). The role of surgical management in active Acanthamoeba is controversial. In prior reports of PK in active AK, there was a high rate of recurrence.810
Received for publication December 10, 2008; revision received September 22, 2009; accepted November 23, 2009. From the *Department of Ophthalmology, SUNY Upstate Medical University, Syracuse, NY; Department of Ophthalmology, SUNYat Buffalo, Buffalo, NY; Department of Ophthalmology, Columbia University, Harkness Eye Institute, New York, NY; and Department of Ophthalmology, University of California, Irvine, CA. This work received support from Research to Prevent Blindness and Lions District 20-Y1. Reprints: Truc H. Nguyen, SUNY Upstate Medical University, Department of Ophthalmology, 550 Harrison Street Suite 340, Syracuse NY 13202 (e-mail: tnguyen709@gmail.com). Copyright 2010 by Lippincott Williams & Wilkins

1000

| www.corneajrnl.com

Cornea  Volume 29, Number 9, September 2010

Penetrating Keratoplasty in Acanthamoeba Keratitis

TABLE 1. Summary of Patient Demographics, Initial Diagnosis, Presentations, and Duration of Symptoms Before Diagnosis
Patient 1 2 3 4 5 6 7 8 9 Age (Yrs) 42 53 20 19 55 52 56 17 28 Sex Female Female Male Female Female Female Female Male Female Initial Diagnosis HSV keratitis Corneal abrasion Bacterial keratitis HZV keratitis Corneal infection HSV HSV keratitis HSV keratitis HSV keratitis Presenting Findings Epithelial defect and granular inltrate Epithelial defect Deep stromal inltrate, radial perineuritis, and satellite lesions Granular inltrate, anterior stromal haze, and perineuritis Perilimbal injection and dendritic keratitis Deep stromal inltrate Central stromal inltrate, dendritic lesions, and iritis Ring inltrate Ring inltrate and stromal edema Duration of Symptoms Before Dx of AK (Wk) 20 2.5 3 4 2.5 7 10 12 5

Dx, diagnosis; HSV, herpes simplex virus; HZV, herpes zoster virus.

With the exception of 1 patient (patient 7), all patients were on combination topical antiamoebic therapy ranging from 2 to 16 weeks before PK as listed in Table 2. One patient (patient 9) was started on chlorhexidine 0.02% and polyhexamethylene biguanide 0.02% preoperatively. All other patients were started on polyhexamethylene biguanide and propamidine isethionate 0.1% and some of the following drugs: chlorhexidine 0.02%, clotrimazole 1%, or neomycin. Preoperative topical regimen was started hourly and tapered to a maintenance dose, typically 4 times daily, according to clinical response. All patients were on preoperative oral ketoconazole or uconazole with the exception of 2 patients (patients 7 and 8). These 2 patients were placed in oral itraconazole postoperatively. Preoperative vision ranged from 20/60 to hand motion (Table 3). PK was performed for the following reasons: worsening of keratitis while on maximal medical therapy, recurrence of keratitis on maintenance medical therapy, concern for scleral extension or depth of stromal involvement, and noncompliance with medical therapy. During PK, care was taken to insure against contamination. Intraoperatively, 2 trays were used to separate contaminated materials and instruments. Host trephination size ranged from 7 to 9 mm depending on the extent of the corneal inltration. The trephination was performed beyond the clinical areas of inltrate, including satellite lesions. Postoperative topical antiamoebic combination was similar to the preoperative treatment. The immediate postoperative topical therapy schedule varied between hourly to 4 times daily dosing. After the immediate postoperative period, antiamoebic medical therapy was tapered according to clinical response. All patients were on maintenance therapy ranging from 2.5 to 10 months. Eight patients were on oral ketoconazole, uconazole, or itraconazole after PK. All patients were treated postoperatively with topical steroids. Follow-up ranged from 8 to 34 months after PK.

All patients reported signicant and immediate pain relief after PK. There were no recurrences of AK after a minimum period of 2 months off of antiamoebic therapy after PK (range 230 months) for all patients. There were no rejections and no graft failure at last follow-up for all patients. The visual results were good with nal best-corrected visual acuity of 20/50 or better (Table 3). One patient (patient 6) had cataract surgery after PK. Two patients had a complicated postoperative course. One patient (patient 5) developed uveitic glaucoma preoperatively that is controlled postoperatively with topical medication. A second patient (patient 8) had prolonged anterior chamber inammation with hypotony followed by optic nerve edema, which resolved after 6 weeks. This patient then developed a peripheral Streptococcus viridans ulcer on the graft, which cleared with topical moxioxacin. Six patients were noted to have developed cataracts after PK.

DISCUSSION
Heightened awareness and better diagnostic techniques have improved the overall prognosis of AK because of the initiation of treatment at an earlier stage.12 The efcacy of treatment for AK is also better because of the introduction of biguanides and diamidines as shown by Duguid et al.13 However, even with the improved efcacy of current available combination treatment, some patients still do poorly with medical therapy despite excellent in vitro drug sensitivities.14 If patients with epithelial and anterior stromal disease are seen at an early stage, there is a high rate of medical cure.15 Epithelial debridement is also effective if the diagnosis is made correctly and the disease is treated at an early stage.6 In this report, our patients presented with more advanced disease that extended into the deep stroma. The keratitis showed progression into the corneal periphery despite intensive treatment or would recur after reducing therapy to a maintenance dose. We also had 1 patient who had poor compliance that progressed because of inadequate therapy. As a result of poor medical response or concern for scleral extension, it was felt that PK was indicated. We report 9 patients with active AK who underwent PK. None of the patients in this series had recurrences or graft failures after PK. Illingworth et al16 in relating their experience
www.corneajrnl.com |

RESULTS
Corneal histopathology for all patients conrmed the diagnosis and showed supercial and deep stromal diseases with cysts. No organisms were noted near the margins of the resection edge in all cases.
q 2010 Lippincott Williams & Wilkins

1001

Nguyen et al

Cornea  Volume 29, Number 9, September 2010

FIGURE 1. Clinical photographs showing AK and results of PK. A, B, A patient with diffuse deep stromal involvement. C, D, A patient with a deep central corneal inltrate with peripheral lesions and result of PK. E, F, A patient with keratoneuritis and result of PK after worsening of keratitis. G, H, Another patient with a deep central corneal inltrate and result of PK.

in a large group of patients with both medical cures and surgical intervention noted good outcomes in 9 subjects who underwent therapeutic PK. These results differ from most previous series that reported high rates of recurrences or graft failure after PK in active AK.810 PK in some of the earlier series were performed in very advanced disease with impending or frank corneal perforation or scleritis.8,9,14 Acanthamoeba can be very difcult to treat when it extends into the sclera.17 Although the patients in our series showed signs of worsening while on combination therapy, none developed perforation or scleritis. AK is a relatively slow process, and so

it was possible to trephine beyond the margin of involvement, making it amenable to surgical resection. Although confocal microscopy was used in 6 patients to help make the diagnosis, we were unable to use this technique to outline the extent of involvement or the size of the trephination. Therefore, the surgical resection margin was based solely on the clinical area of corneal inltrate seen at the time of surgery. We believe that performing PK before scleral or peripheral corneal extension minimizes the risk of recurrence and poor outcome. Postoperatively, patients were monitored for recurrence of AK based on clinical parameters of pain, degree of inammation, presence of persistent epithelial defect,
q 2010 Lippincott Williams & Wilkins

1002

| www.corneajrnl.com

Cornea  Volume 29, Number 9, September 2010

Penetrating Keratoplasty in Acanthamoeba Keratitis

TABLE 2. Summary of Antiamoebic Medical Treatments

Duration of Preoperative Medical Therapy (Wk) 4 16 2 2 13 4 0 2 6 Duration of Postoperative Medical Therapy (Mo) 4 6.5 4 6 10 10 2.5 6 6

Preoperative Medical Therapy Topical Neomycin, PHMB, and propamidine Neomycin, PHMB, and propamidine Neomycin, PHMB, and propamidine Neomycin, PHMB, and propamidine Clotrimazole, neomycin, PHMB, and propamidine Clotrimazole, neomycin, PHMB, and propamidine None Chlorhexidine PHMB Propamidine Chlorhexidine and PHMB Oral Ketoconazole Ketoconazole Ketoconazole Ketoconazole Ketoconazole Ketoconazole None None Fluconazole

Postoperative Medical Therapy Topical Neomycin, PHMB, and propamidine PHMB and propamidine Chlorhexidine, PHMB, and propamidine Chlorhexidine, PHMB, and propamidine Clotrimazole, neomycin, and PHMB Clotrimazole, PHMB, and propamidine None Chlorhexidine, PHMB, and propamidine Chlorhexidine and PHMB Oral Ketoconazole Ketoconazole Fluconazole Ketoconazole Ketoconazole Ketoconazole Itraconazole Itraconazole None

Patient 1 2 3 4 5 6 7 8 9

PHMB, polyhexamethylene biguanide.

TABLE 3. Postoperative Results of PK

Patient 1 2 3 4 5 6 7 8 9 Preoperative BCVA HM CF HM 20/60 20/400 CF 20/400 HM 20/200 Indication for PK Poor compliance with progressive keratitis Recurrent keratitis with progression Deep keratitis with peripheral extension Progressive keratitis with peripheral extension Recurrent keratitis with progression Progressive keratitis Therapeutic and diagnostic PK because of progressive keratitis Progressive keratitis Progressive keratitis F/U Period After PK (Mo) 34 21 26 14 14 12 16.5 11 8 Duration of F/U Off Antiamoebic Rx (Mo) 30 14.5 22 8 4 2 14 5 2 Final BCVA 20/25 20/30 20/15 20/20 20/50 20/40 20/30 20/30 20/50

BCVA, best-corrected visual acuity; CF, count ngers; F/U, follow-up; HM, hand motion; Rx, treatment.

recurrence of corneal inltrate, and response to taper of antiamoebic medical therapy. Although not used postoperatively in this series, confocal microscopy may also be helpful in determining recurrence if the postoperative course is atypical. Reported complications of advanced AK include glaucoma18 and cataracts.8 Kelley et al18 reported the development of glaucoma in 30% of AK with poor outcomes.16 Ficker et al8 reported cataracts in 50% of eyes that underwent PK after medical control and in 100% of eyes that underwent PK during the acute stage. In the current series, 1 patient developed glaucoma. Cataracts developed in 6 patients, with 1 requiring cataract extraction. Our case series is limited by a small sample size and the various treatment protocols used at different institutions. In addition, because of the wide range of time to diagnosis, 2.5 weeks to 5 months, it was difcult to determine a minimum duration of treatment prior to recommending surgery. Therefore, surgery was recommended on an individual basis as per the criteria discussed above. In conclusion, we feel that therapeutic PK combined with current medical therapy is a viable option for patients
q 2010 Lippincott Williams & Wilkins

with worsening AK while on maximum medical treatment and that grafting should be considered before the development of scleritis or peripheral corneal extension. REFERENCES
1. Joslin CE, Tu EY, McMahon TT, et al. Epidemiological characteristics of a Chicago-area Acanthamoeba keratitis outbreak. Am J Ophthalmology. 2006;142:212217. 2. Thebpatiphat N, Hammersmith KM, Rocha FN, et al. Acanthamoeba keratitis. A parasite on the rise. Cornea. 2007;26:701705. 3. Parmar DN, Awwad ST, Petroll WM, et al. Tandem scanning confocal corneal microscopy in the diagnosis of suspected Acanthamoeba keratitis. Ophthalmology. 2006;113:538547. 4. Larkin DFP, Kilvington S, Dart JKG. Treatment of Acanthamoeba keratitis with polyhexamethylene biguanide. Ophthalmology. 1992;99: 185191. 5. Alizadeh H, Silvany RE, Meyer DR, et al. In vitro amoebicidal activity of propamidine and pentamidine isethionate against Acanthamoeba species and toxicity to corneal tissues. Cornea. 1997;16:94100. 6. Brooks JG Jr, Coster DJ, Badenoch PR. Acanthamoeba keratitis. Resolution after epithelial debridement. Cornea. 1994;13:186189. 7. Cremona G, Carrasco MA, Tytiun A, et el. Treatment of advanced Acanthamoeba keratitis with deep lamellar keratectomy and conjunctival ap. Cornea. 2002;21:705708.

www.corneajrnl.com |

1003

Nguyen et al

Cornea  Volume 29, Number 9, September 2010

8. Ficker FA, Kirkness C, Wright P. Prognosis for keratoplasty in Acanthamoeba keratitis. Ophthalmology. 1993;100:105110. 9. Bacon AS, Frazer DG, Dart JKG, et al. A review of 72 consecutive cases of Acanthamoeba keratitis, 1984-1992. Eye. 1993;7:719725. 10. Hargrave SL, McCulley JP, Husseini Z. Results of a trial of combined propamidine isethionate and neomycin therapy for Acanthamoeba keratitis. Ophthalmology. 1999;106:952957. 11. Awwad ST, Parmar DN, Heilman M, et al. Results of penetrating keratoplasty for visual rehabilitation after Acanthamoeba keratitis. Am J Ophthalmology. 2005;140:10801084. 12. Bacon AS, Dart JKG, Ficker LA, et al. Acanthamoeba keratitis. The value of early diagnosis. Ophthalmology. 1993;100: 12381243.

13. Duguid IGM, Dart JKG, Morlet N, et al. Outcome of Acanthamoeba keratitis treated with polyhexamethyl biguanide and propamidine. Ophthalmology. 1997;104:15871592. 14. Perez-Santonja JJ, Kilvington S, Hughes R, et al. Persistently culture positive Acanthamoeba keratitis. Ophthalmology. 2003;110:15931600. 15. Wilhelmus KR, Jones DB, Matoba AY, et al. Bilateral Acanthamoeba keratitis. Am J Ophthalmology. 2008;145:193197. 16. Illingworth CD, Cook SD, Karabatsas CH, et al. Acanthamoeba keratitis: risk factors and outcome. Br J Ophthalmology. 1995:79:10781082. 17. Lee GA, Gray TB, Dart JKG, et al. Acanthamoeba sclerokeratitis: treatment with systemic immunosuppression. Ophthalmology. 2002;109:11781182. 18. Kelley PS, Dossey AP, Patel D, et al. Secondary glaucoma associated with advanced Acanthamoeba keratitis. Eye Contact Lens. 2006;32:178182.

1004

| www.corneajrnl.com

q 2010 Lippincott Williams & Wilkins