Treatment of infectious keratitis with riboflavin and ultraviolet-A irradiation Elsie Chan, FRANZCO, Grant R. Snibson, FRANZCO, Laurence Sullivan, FRANZCO

We report 4 eyes with infectious keratitis treated with riboflavin/ultraviolet-A irradiation (corneal collagen crosslinking [CXL]) in addition to medical treatment. In 2 eyes with bilateral keratitis, the fellow eye was treated with medical treatment alone. The other 2 eyes had refractory keratitis. The results suggest that CXL may be more worthwhile in cases refractory to conventional medical treatment. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2014; 40:1919–1925 Q 2014 ASCRS and ESCRS

Infectious keratitis is a major cause of corneal blindness worldwide.1 Although many cases can be successfully managed with topical agents, an increasing number of case reports and case series have used a combination of riboflavin and ultraviolet-A (UVA) irradiation as primary treatment (with or without the addition of conventional medical treatment)2–4 or as additional treatment in refractory keratitis.3–11 Riboflavin and UVA have been shown to increase the strength of corneal tissue and are currently used in corneal collagen crosslinking (CXL) for the treatment of keratoconus.12,13 In addition, riboflavin and UVA irradiation have been shown to have antimicrobial properties. In vitro studies have demonstrated its bactericidal

Submitted: May 31, 2014. Final revision submitted: June 17, 2014. Accepted: June 17, 2014. From the Centre for Eye Research Australia, University of Melbourne, and the Royal Victorian Eye & Ear Hospital, Melbourne, Australia. Financial support for this study received from the Royal Victorian Eye and Ear Hospital, Melbourne, Australia Small Grants Committee. The Centre for Eye Research Australia receives operational infrastructure support from the Victorian government. The Medical Photography and Imaging Centre at the Royal Victorian Eye and Ear Hospital Melbourne, Australia, provided technical support. Corresponding author: Laurence Sullivan, FRANZCO, 32 Gisborne Street, East Melbourne, Victoria 3002, Australia. E-mail: laurence. [email protected] Q 2014 ASCRS and ESCRS Published by Elsevier Inc.

effect against isolates of Staphylococcus aureus, S epidermidis, Pseudomonas aeruginosa, Streptococcus pneumoniae, and methicillin-resistant S aureus.14–16 Conversely, CXL does not eradicate Candida albicans, Fusarium species, Aspergillus fumigatus,14,17 or Acanthamoeba18 in vitro, although it may enhance the effect of antifungal medications.17 Corneal CXL also increases the cornea's resistance to degradative enzymes; in porcine eyes, the digestion time doubles.19 In numerous circumstances, CXL may be more advantageous than conventional treatment in managing infections. These include cases in which no organism is isolated to guide medical treatment, infections with significant stromal lysis, cases in which compliance with treatment regimens are problematic, or in geographical locations in which there is limited availability of appropriate topical antibiotics. There is also growing concern about the increasing resistance of microorganisms to standard antibiotics.20 We previously treated a patient with refractory fungal keratitis caused by Alternaria species with CXL and noted a rapid clinical improvement. In this report, we describe the results in 4 cases in which CXL was used as adjunctive therapy in the treatment of infectious keratitis as part of a prospective clinical trial. CASE REPORTS Treatment Protocol The cases presented are part of a pilot study being conducted at the Royal Victorian Eye & Ear Hospital (RVEEH), Melbourne, Australia. The aim of the pilot study is to determine the feasibility and appropriateness of a 0886-3350




Figure 1. Case 1: Right eye (treated with conventional medical treatment only) at presentation (a) and after 1 month (b). Left eye prior to CXL (c) and 1 month after CXL (d).

randomized controlled trial of CXL in the management of infectious keratitis. The study was approved by the hospital's Human Research and Ethics Committee, and the conduct of this study adheres to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants prior to treatment. The size of the pilot study was limited to 10 eyes by our Ethics Committee, and the outcome in the first 4 treated eyes are presented here. Patients were eligible for the study if they had a clinical diagnosis of microbial keratitis of at least moderate severity (defined by a corneal infiltrate with an overlying epithelial defect measuring a minimum of 3.0 mm in its shortest axis). Exclusion criteria included a history of herpes simplex or herpes zoster infection, the presence of a descemetocele, or a corneal perforation in the affected eye. Patients unable to tolerate the CXL treatment or comply with the follow-up regimen were also excluded. Corneal CXL was performed according to a modification of the Dresden protocol. Topical anesthetic (oxybuprocaine hydrochloride 0.4%) was instilled 3 times over a 10-minute period. A lid speculum was inserted, and epithelial debridement to 2.0 mm beyond the infiltrate was performed with a blade (Sharpoint straight scleral blade, Surgical Specialties Co) and handle. Riboflavin eyedrops (Ribolink Isotonic, riboflavin 5-phosphate 0.1% plus 20% dextran T500) was applied to the cornea approximately every 1 to 3 minutes over an initial soaking period of 30 minutes and then for a further 30 minutes during UVA treatment. Ultrasound (US) pachymetry (AL 100, Tomey Corp.) was performed every 10 minutes in the affected area or in an unaffected area in which the former was not possible. If the corneal thickness was less than 400 mm, hypotonic riboflavin (Ribolink Hypotonic, riboflavin-5-phosphate 0.1%) was used in place of isotonic riboflavin. Ultraviolet irradiation did not proceed until the corneal thickness was more than 400 mm. The UV-X device (UV-X 1000, IROC Innocross AG) was used to deliver UVA irradiation of 365 nm G 10 (SD) wavelength via a 9.0 mm aperture at 5 cm from the apex of the cornea. The output of the UV source was confirmed before and after every treatment using the UV Light Meter (Model YK-34UV, Lutron Electronic Enterprise Co. Ltd.). During the

irradiation phase, the limbus was masked using an instrument wipe (Visiwipe Instrument Wipe, Beaver-Visitec International) with a 10.0 mm central opening cut using a sterile 10.0 mm trephine (Medtronic Ophthalmics). After irradiation, the eye was washed with a sterile balanced salt solution (Alcon Laboratories, Inc.). No contact lens was applied. Following treatment, the frequency and use of topical medications were in accordance with clinician preference and the hospital's usual clinical practice.

Case 1 An 87-year-old man was referred to the emergency department at RVEEH on November 2, 2011, with 4 days of decreased vision. He had a history of glaucoma and recent cataract surgery in both eyes, the latter complicated by bilateral postoperative macular edema. He had been treated with prednisolone acetate 1.0% (Prednefrin Forte) and ketorolac 0.5% (Acular) for 2 weeks prior to this presentation. The systemic history was significant for end-stage renal failure. On presentation, the corrected distance visual acuity (CDVA) was light perception in both eyes. He had bilateral microbial keratitis characterized by dense infiltrates and stromal thinning (Figure 1, a and c). A diagnostic corneal scrape was performed, and ofloxacin 0.3% eyedrops (Ocuflox) were administered to both eyes every hour. After S pneumoniae was isolated from the corneal scrapes the following day, oral moxifloxacin 400 mg daily, topical vancomycin 5.0% (prepared by the RVEEH Pharmacy using vancomycin hydrochloride 500 mg [DBL Vancomycin Hydrochloride for Intravenous Infusion] diluted in water for injection) to both eyes and fluorometholone acetate 0.1% (Flarex) to the right eye were added to the treatment regimen. Two days after presentation, CXL was performed in the left eye as this eye was considered the more severely affected. Slitlamp examination using fluorescein sodium (Fluorets 1 mg paper strips, Chauvin Pharmaceuticals) had not been performed within 7 hours prior to the CXL. Anterior segment ocular coherence tomography (OCT) (Visante, Carl Zeiss Meditec AG) showed a thinned cornea measuring




Table 1. Outcome parameters in treated and untreated eyes. Baseline

1 Week

1 Month

3 Months


Infiltrate CDVA (mm)

Epithelial Epithelial Epithelial Epithelial Defect Infiltrate Defect Infiltrate Defect Infiltrate Defect (mm) CDVA (mm) (mm) CDVA (mm) (mm) CDVA (mm) (mm)

1, RE 1, LE (CXL) 2, RE (CXL) 2, LE 3 (CXL) 4 (CXL)

LP LP HM LP HM 20/800

6.5 x 6.6 O8.0 x 8.0 5.6 x 6.4 6.2 x 6.4 4.9 x 4.9 3.1 x 3.6

8.0 x 8.0 8.0 x 8.0 6.2 x 6.2 5.5 x 5.5 4.9 x 5.6 3.1 x 3.6

HM CF HM HM HM 20/125

Resolved Resolved 5.5 x 5.5 5.0 x 5.5 5.0 x 6.0 2.4 x 2.7

6.4 x 5.8 O8.0 x 8.0 2.8 x 3.2 5.2 x 4.5 5.2 x 5.4 Healed

HM HM CF CF HM 20/60

Resolved Resolved 2.0 x 2.0 !1mm Scar only 2.6 x 3.2

4.6 x 4.6 7.0 x 5.7 2.5 x 2.5 !1mm 4.6 x 4.6 Healed

HM HM 20/200 20/400 20/250 20/60

Resolved Resolved Scar only Scar only Scar only Scar only

3.0 x 2.3 3.0 x 3.1 Healed Healed 1.0 x 2.2 Healed

CDVA Z corrected distance visual acuity; CF Z counting fingers; CXL Z collagen crosslinking; HM Z hand motion; LP Z light perception

260 mm with a full-thickness infiltrate. A combination of isotonic and hypotonic riboflavin was used to increase the corneal thickness, although reliable intraoperative US pachymetry measurements could not be obtained. Fluorometholone acetate 0.1% was started the following day. By the fifth day, the infiltrates in both eyes were resolving, leaving only a stromal haze. Due to poorly healing epithelial defects at 1 month, a protective ptosis was induced using botulinum A (5 international units) injected into the left levator palpebrae superioris (Figure 1, b and d). After 2 months, the epithelial defects remained 4.2 mm  3.5 mm in the right eye and 4.4 mm  4.1 mm in the left eye and bandage contact lenses (Purevision, Bausch & Lomb Pty Ltd.) were placed to aid epithelial healing. At the final examination, 3 months after presentation, the epithelial defects remained 3.0 mm  2.3 mm in the right eye and 3.0 mm  3.1 mm in the left eye (Table 1). Unfortunately, the patient died from complications of end-stage renal failure, which were not considered to be related to the microbial keratitis treatment.

Case 2 A 70-year-old woman presented to the emergency department at RVEEH on February 18, 2012, with pain and reduced vision in the right eye for 2 days. She had a history of soft contact lens wear. On presentation, the CDVA was light perception in the right eye and 20/40 in the left eye. There was a large corneal infiltrate associated with a 3.0 mm hypopyon (Figure 2, a). Topical ofloxacin drops were prescribed. A diagnostic corneal scrape was performed and isolated P aeruginosa, and anterior segment OCT (AS-OCT) showed a corneal infiltrate extending to a depth of 430 mm. Three days after presentation, CXL was performed. Slitlamp examination using fluorescein sodium had taken place 3 hours prior to the treatment. Following CXL, frequent topical antibiotic treatment was continued and fluorometholone acetate 0.1% eyedrops were started 3 days later. On February 24, the patient returned to the emergency department with a 1-day history of decreased vision in the fellow (left) eye (Figure 2, d). The UDVA was light perception, and there was a large corneal infiltrate with a 1.0 mm hypopyon. A corneal scrape again isolated P aeruginosa, and intensive topical ofloxacin was started, followed by the addition of topical fluorometholone acetate 0.1% on day 3. This eye was not treated with CXL.

The hypopyon in the right eye resolved by day 11 (day 9 after CXL) and in the left eye by day 6. The epithelial defect resolved by 10 weeks in the right eye and 7 weeks in the left eye (Table 1). The right eye developed 2 clock hours of superficial corneal vascularization in the superior cornea (Figure 2, b, c, e, and f). Deep anterior lamellar keratoplasty was performed in the right eye in November 2012 for visual rehabilitation. At the most recent follow-up in January 2014, the CDVA in the right eye was hand motion (HM). The corneal transplant was clear, but a visually significant posterior subcapsular cataract had developed. The CDVA in the left eye was 20/100 with a subjective refraction of C5.00 diopters sphere.

Case 3 A 52-year-old man presented on November 12, 2011, with a 6-day history of an irritated left eye. He wore contact lenses and had been scuba diving overseas. He had been treated with ofloxacin and natamycin eyedrops as well as oral cefadroxil and methylprednisolone prior to his return to Australia. On presentation, the CDVA in the left eye was HM. There was a large infiltrate and an overlying epithelial defect (Figure 3, a). The treatment regimen was changed to intensive ofloxacin eyedrops and chloramphenicol eye ointment (Chlorsig). Five days later, there was no clinical improvement and topical vancomycin was introduced. Microbiological testing remained negative despite corneal scrapes on 4 occasions and 1 corneal biopsy. Anterior segment OCT showed an infiltrate depth of 440 mm. As there were no signs of improvement after 10 days of topical treatment, CXL was performed. No fluorescein sodium had been instilled in the eye on the day of treatment. By day 12 after CXL, the infiltrate was resolving, leaving only a haze. The epithelial defect persisted for 4 months (Table 1, Figure 3, b and c). Two years later, a penetrating keratoplasty was performed for visual rehabilitation, which was complicated by suture loosening. This was managed with resuturing after 2 weeks and a course of oral prednisolone. Again, there was a persistent epithelial defect that did not heal until 2.5 months after surgery.

Case 4 A 51-year-old man presented on September 19, 2012, with a 5-day history of a red, painful left eye associated with




Figure 2. Case 2: Right eye prior to CXL (a), after 3 weeks (b), and after 6 months (c). Left eye (treated with conventional medical treatment only) at baseline (d), after 2 weeks (e), and after 6 months (f).

decreased vision. He wore contact lenses and had been playing water polo. He had been treated with fluorometholone acetate 0.1% and acyclovir ointment by an ophthalmologist prior to his presentation. On examination, the UDVA was 20/800. There was a ringshaped stromal infiltrate with an associated epithelial defect consistent with a clinical diagnosis of Acanthamoeba keratitis. This diagnosis was confirmed using confocal microscopy, the detection of Acanthamoeba cysts on direct microscopy, and from cultures of corneal scrapings. Treatment was initiated with chlorhexidine 0.02% (prepared by RVEEH pharmacy using chlorhexidine gluconate 0.1% diluted in water for injection) and propamidine (Brolene) drops administered every hour. Twelve days later, the pain was unchanged, although there was some clinical improvement. Fluorometholone acetate 0.1% drops were started to reduce inflammation. Over the following month, the eye continued to recover, with closure of the epithelial defect and reduction of the infiltrate. The CDVA improved to 20/32. However, 10 weeks after the initial presentation, the CDVA decreased to 20/400 with an increase in corneal edema. Despite intensification of the topical treatment and subsequent cessation of the fluorometholone acetate, there were ongoing signs of active infection with corneal edema, keratic precipitates, and anterior chamber cells. A repeat corneal scrape confirmed the persistence of Acanthamoeba species. By February 1, 2013, the CDVA was 20/800 with a 3.1 mm  3.6 mm epithelial defect and 3.1 mm  3.6 mm infiltrate. There was significant pain and conjunctival injection. The depth of the infiltrate on AS-OCT was 360 mm. Due to

concerns about the inadequate treatment of the infection with topical agents, CXL was performed. No fluorescein sodium had been instilled in the eye on the day of treatment. While the preoperative pachymetry was 570 mm, this decreased to below 300 mm after 20 minutes of isotonic riboflavin drops, requiring the use of hypotonic riboflavin prior to starting treatment once the corneal thickness increased to 427 mm. On the day following CXL, the patient remained in severe pain. By week 1, he reported significant symptomatic improvement, with the CDVA improving to 20/125 and a reduction in the size of the infiltrate and closure of the epithelial defect. The conjunctival injection also improved. Two months after CXL, the propamidine was stopped, with only a stromal scar and punctate epithelial erosions observed on examination, although mild conjunctival injection remained. Three months after CXL, the CDVA had improved to 20/60, and there was no further conjunctival injection (Table 1). Chlorhexidine was stopped 6 months after CXL. At the most recent examination in September 2013, the patient was asymptomatic and the CDVA was 20/50.

DISCUSSION Numerous case reports and case series support the use of CXL in bacterial keratitis, with more variable outcomes in cases of fungal, Acanthamoeba, and viral keratitis.2–11,21 Although it is difficult to draw conclusions from isolated case reports, in 2 of the cases that we



Figure 3. Case 3: Prior to CXL (a), after 1 month (b), and after 4 months (c).

report, we observed a clinical improvement following the introduction of CXL in patients in whom the keratitis had failed to respond to conventional treatment. However, in 2 unusual cases of bilateral keratitis caused by sensitive organisms in which 1 eye was treated with CXL in addition to conventional therapy, no difference in outcome was observed. Several possible effects of CXL support its use in the treatment of infectious keratitis. Ultraviolet irradiation has been shown to have a dose-dependent ability to directly destroy microorganisms,22 whereas activated riboflavin can produce reactive oxygen species that


are also toxic to microorganisms.23,24 Corneal CXL also increases the resistance of the corneal stroma to enzymatic degradation,19 which may reduce the progression of corneal melting and prevent corneal perforation. Another potential advantage of CXL is its toxic effect on inflammatory cells,25 which may limit the inflammatory response to infection, the attendant tissue damage, and subsequent scarring. A prospective study by Price et al.3 examined 40 cases of infectious keratitis treated with CXL using different UVA irradiation times. The authors concluded that the success rate was higher for cases of bacterial keratitis than for cases of fungal or Acanthamoeba keratitis, although some cases required repeated treatment. In addition, a correlation between the depth and size of the infiltrate and the time to resolution was suggested, with a greater effect noted in cases in which the infiltrate depth was less than 250 mm or the infiltrate was less than 2.5 mm in diameter or less than 3.5 mm2 in area. In a prospective trial comparing CXL with conventional medical treatment and conventional medical treatment alone (control group), Said et al.8 did not find any between-group difference in the time to resolution of infections associated with corneal melting. However, 3 cases in the control group were complicated by corneal perforation and a fourth case recurred. This led the authors to suggest that CXL may have a benefit as an adjuvant treatment in reducing the risk for complications from severe infectious keratitis. In Cases 1 and 2, the time for the infiltrates to resolve was similar in both crosslinked and non-crosslinked eyes. This may relate to a relative lack of efficacy of CXL, particularly in Case 2 in which the infiltrate was deeper or, conversely, to the effectiveness of topical antibiotic treatment with sensitive organisms. In Australia, bacterial resistance to fluoroquinolones remains low.26,27 An alternative explanation for our results may be the use of fluorescein sodium 7 hours and 3 hours, respectively, prior to CXL in these 2 cases. Richoz et al.28 reported that fluorescein sodium 2.0% may compete with riboflavin for the absorption of UVA irradiation and may thus reduce the antimicrobial effect of CXL. The minimum length of time that should be observed between fluorescein sodium instillation and CXL is not known. Early relief of pain following CXL was noted in the 4 cases, a finding also reported by Makdoumi et al.4 Although possibly reflecting the positive impact of CXL on the infection itself, the reduction of pain may also be explained by the loss of the subepithelial and anterior stromal nerve fibers following CXL.29 The treatment of Acanthamoeba keratitis is often more challenging than the treatment of other forms of infectious keratitis, with a prolonged disease




course often necessitating many months of intensive treatment. In vitro studies have shown that riboflavin and UVA (3mW/cm2 for 30 or 60 minutes) does not eradicate Acanthamoeba strains.18 Despite these findings, Khan et al.30 report the successful treatment of 3 cases of Acanthamoeba keratitis with 2 CXL treatments. Their cases were retreated after 1 to 2 weeks when the rate of healing was noted to have reduced. This may reflect the relative resistance of Acanthamoeba cysts to medical treatment compared with trophozoites. Price et al.3 did not find evidence of a response to CXL in 2 cases of Acanthamoeba keratitis. Despite the reported success of CXL in some cases of infectious keratitis, there are potential safety issues. A minimum corneal thickness of 400 mm is recommended during CXL to protect the endothelium from toxicity.31 However, the measurement of corneal thickness in the presence of active keratitis is not always possible during the treatment. In cases of deep infiltrates and stromal melting, endothelial damage may be less relevant given that penetrating keratoplasty is often required in this setting. Nevertheless, care must be taken, especially in cases in which the infection is confined to the anterior stroma. We would also recommend masking the limbus as limbal stem cells are susceptible to damage when the infection and the irradiation involve the peripheral cornea. There remains a lack of evidence to establish the efficacy, safety, and optimal treatment protocols for the management of infectious keratitis with CXL. Studies reported to date have mostly used modifications of the Dresden protocol12 established for the treatment of progressive keratoconus. The presence of a corneal infiltrate (or scarring) may have an effect on the penetration of riboflavin and UVA, which has not been quantified.30 Uneven penetration may also lead to refractive consequences.2 Based on current information, we suggest that CXL may be more useful in cases that are refractory to conventional medical treatment. REFERENCES 1. Whitcher JP, Srinivasan M, Upadhyay MP. Corneal blindness: a global perspective. Bull World Health Org 2001; 79:214–221. Available at: Accessed July 1, 2014 2. Makdoumi K, Mortensen J, Sorkhabi O, Malmvall B-E, Crafoord S. UVA-riboflavin photochemical therapy of bacterial keratitis: a pilot study. Graefes Arch Clin Exp Ophthalmol 2012; 250:95–102 3. Price MO, Tenkman LR, Schrier A, Fairchild KM, Trokel SL, Price FW Jr. Photoactivated riboflavin treatment of infectious keratitis using collagen cross-linking technology. J Refract Surg 2012; 28:706–713

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First author: Elsie Chan, FRANZCO Centre for Eye Research Australia, University of Melbourne, and the Royal Victorian Eye & Ear Hospital, Melbourne, Australia

Treatment of infectious keratitis with riboflavin and ultraviolet-A irradiation.

We report 4 eyes with infectious keratitis treated with riboflavin/ultraviolet-A irradiation (corneal collagen crosslinking [CXL]) in addition to medi...
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