Fungal keratitis is a devastating eye infection. Two basic forms have been recognized; that is, hyaline filamentous fungi (eg, Fusarium species, Aspergillus species, and phaeohyphomycetes, which exist mainly in tropical and subtropical zones) and yeast fungi (eg, Candida albicans). The key predisposing risk factor for filamentous fungi is trauma by soil or plant pathogens. Other risk factors include contact lens use (in particular with soft monthly lenses) or previous corticosteroid use.1–4 Usually, the course of the filamentous fungal infection does not include penetration of the intact eye epithelium. The invasion occurs as a result of trauma, which happens in 40% to 60% of patients. Other predisposing factors for invasion include contact lens, a history of ocular surgery, and ocular surface disease.
The prevalence of fungal keratitis may be in up to 50% of the patients who have culture-proven microbial keratitis, in particular in tropical and subtropical environments.2 The incidence depends on the degree of urbanization and ranges from 6% to 56%. It is predominant in the younger age group (16 to 49 years) and among men.3
Fusarium species have been identified in patients who use soft monthly contact lenses. From mid-2005 to approximately July 2006, a multicountry outbreak of contact lens–associated keratitis caused by Fusarium species occurred. Up to that time, filamentous fungi was infrequently linked to contact lens–associated keratitis.2
Fungal infection can be diagnosed using multiple methods. These include clinical presentation, noninvasive methods (confocal microscopy), and invasive methods (culture of corneal biopsies or polymerase chain reaction [PCR]). In clinical examinations, we can see multifocal granular gray–white “satellite” stromal infiltrates, often with intact epithelium above the infiltrate and a pyramidal, often retrocorneal, adherent hypopyon.2,5
Confocal microscopy aids not only in the diagnosis, but may also be used to check the response to treatment.2,6 If the diagnosis is established quickly, the prognosis will be better and complete recovery is possible. Complications of fungal infection depend on how far the infection extends into the eye. The infection might progress to endophthalmitis, complete vision loss, and enucleation of the eye.1
The treatment of fungal keratitis requires the use of antifungals, either topical, intrastromal, or anterior chamber washing and alone or in combination with systemic antifungals. In severe challenging cases that are refractory to medical treatment or lead to complications, surgical interventions are required to prevent corneal perforation or further extension of the infection.3
We explored appropriate diagnostic and therapeutic measures for a complicated case of a very severe F solani keratitis resulting from delayed diagnosis.
A 23-year-old woman presented with poor vision and pain in the right eye. Visual acuity in the right eye was hand motions (HM) (−2.0 logarithm of the minimum angle of resolution [logMAR]). She had a history of wearing soft monthly contact lenses while swimming in a “pond” in Mexico. She was referred to our department in December 2013 after she had been treated with multiple anterior chamber washings using voriconazole and amphotericin B and application of topical steroids. Light biomicroscopy showed gray–white “satellite” stromal infiltrates and endothelial decompensation (Figure 1, A).
Confocal microscopy 1 day after the admission showed hyphae as bright branches and broad-based hyperreflective lines that ran, in part, parallel to one another (Figure 1, B). Riboflavin corneal crosslinking with anterior chamber washing using voriconazole, vancomycin, and ceftazidime were performed. One day after cessation of the topical steroids, the ulcer, endothelial decompensation, diffuse subepithelial infiltration, and retrocorneal precipitation markedly increased (Figure 1, C).
An emergency nonmechanical excimer laser–assisted penetrating keratoplasty (PKP) with a graft size of 8.0 to 8.1 mm, aqueous humor aspiration, and anterior chamber washing were performed. On the fourth postoperative day, the corrected distance visual acuity (CDVA) was HM and the patient again reported eye pain with a mild headache. The PCR showed no growth of herpes simplex virus DNA. Light biomicroscopy showed remarkable irritation of the anterior chamber with hypopyon (1.0 mm) and a retrocorneal membrane (Figure 2, A). Two days later, systemic terbinafine hydrochloride 250 mg (Terbinafine) was started, replacing the voriconazole.
One week after the first PKP, a second PKP with a larger graft (10.5 to 11.0 mm) combined with intrastromal antifungal injection was performed. This was followed by 2 anterior chamber washings using a triple dose of vancomycin, ceftazidime, and voriconazole to prevent endophthalmitis. During the 2 postoperative days, the CDVA was HM and the patient again reported eye pain and a headache; a psychiatric consultation was scheduled. The histological and microbiological tests showed evidence of fungal infection with F solani organism. Topical natamycin 5.0% was added to the treatment. On the third postoperative day, light biomicroscopy showed hypopyon and fibrin. A daily anterior chamber washing with amphotericin B and antibiotics combined with an intravitreal amphotericin B injection were performed for 1 week. Light biomicroscopy still showed fibrin and hypopyon and retrocorneal pigmented precipitates.
Daily anterior chamber washing with amphotericin B and intracameral injection of vancomycin, ceftazidime, voriconazole, and amphotericin B were performed for the next 2 weeks. During that time, the sensitivity tests showed a resistance to voriconazole, posaconazole, and terbinafine and a high dose of amphotericin B was recommended.
Light biomicroscopy showed retrocorneal infiltration with occlusive membrane in the pupil and a choroidal hematoma, subretinal bleeding (Figure 2, B), corneal infiltration, erosion, and posterior synechiae. A third PKP with a graft size of 12.0 to 13.0 mm, a prophylactic pars plana vitrectomy (PPV), subretinal lavage, lens extraction (without intraocular lens implantation), and silicone oil tamponade were performed.
On the first postoperative day, there was no pain and the ocular examination showed a little fibrin in the anterior chamber. In the following days, multiple anterior chamber washings were done. The patient was discharged 2 weeks later and prescribed topical eyedrops of prednisolone acetate, fluoroquinolone antibiotic (Vigamox), polyhexanide (Lavasept), and amphotericin B 1.0%, all 5 times a day, as well as oral prednisolone.
One month later, the ocular examination showed corneal erosion and caudal proliferative vitreoretinopathy detachment under the silicone oil. A 20-gauge repeat PPV with silicone exchange and amniotic membrane transplantation as a patch were performed, and a therapeutic contact lens was applied (Figure 2, C).
One month later, the CDVA was counting fingers (−1.9 logMAR). Examination showed a small ulcer in the graft. On ultrasonography, the retina was attached under silicone oil. The amniotic membrane patch was removed and a new one, which covered the entire cornea, was inserted. Light biomicroscopy 1 month after the second amniotic membrane patch showed a partially integrated membrane (Figure 3, A). In the following 3 months, there was no significant change in the CDVA (HM).
Eleven months later, the corneal epithelium was closed and the ocular examination showed aphakia, an attached retina, and epiretinal gliosis. Therefore, a third 23-gauge PPV with membrane peeling was performed.
At the last follow-up (4 years later), the visual acuity was HM and the patient had no pain. Light biomicroscopy showed the beginning of endothelial decompensation and peripheral vascularization in an otherwise quiet eye (Figure 3, B).
Fungal keratitis is defined as mycosis of the cornea and can be caused by multiple types of fungi.2 Fungal keratitis is a major cause of visual loss in developing countries.7 In study by Galarreta et al.,8 yeasts were isolated from 25 (34.8%) of 66 patients with fungal keratitis and filamentary fungi were isolated in 26 patients (39.4%). The latter included 12 patients (18.1%) with Fusarium species (7 patients [10.6%] with F solani) and 7 (10.6%) with Aspergillus species.
Typical manifestations of fungal keratitis infection appear within 24 to 36 hours after trauma with ocular pain, redness, and decreased vision.9 The early microscopic features consist of fine or coarse granular infiltrates in the epithelium and anterior stroma, with minimal cellular reaction initially. Advanced cases show severe inflammation, corneal ulcer, hypopyon, and the existence of fungal hyphae within the corneal stroma that are not visible clinically.2 Hyphae can multiply in an extensive way without inducing much cellular infiltration.9 The pathophysiology of Fusarium relates to its mycotoxin and its ability to replicate at 35°C.9,10
The diagnosis can be made by in vitro cultivation (fungal culture), PCR, and histological investigation. However, to establish a fast and early diagnosis, we recommend the noninvasive method of confocal microscopy before the results of an in vitro technique are available.6 Confocal microscopy plays an important role in early diagnosis of filamentous infection. It is reported to have a sensitivity of approximately 94% and a specificity of approximately 78%.6,11,12 This allows quick determination of the cause and whether to start or modify therapy accordingly.12
Keratitis caused by Fusarium species is still considered not easy to treat, even when intensive topical and systemic antifungal medications are used. Therefore, surgical measures such as PKP should be an early consideration.2
Conservatively, a drug is considered effective if it can penetrate the eye wall, thus reaching a high level of antifungal activity in the stroma and anterior chamber.2 Epithelial removal is necessary for amphotericin B to penetrate the eye. The drug of choice to treat a Fusarium keratitis is topical natamycin 5.0%. In addition, voriconazole and terbinafine hydrochloride 250 mg are recommended.13,14 Antifungals can be used topically alone as monotherapy (eg, econazole, amphotericin B, ketoconazole, itraconazole, fluconazole, or voriconazole) or in combination with systemic antifungals (eg, voriconazole, itraconazole, or fluconazole).1,3,14
As soon as the diagnosis of Fusarium keratitis is established, medical therapy with triple antifungal concentration should be started.15 However, approximately 70% of Fusarium keratitis patients who have deep lesions do not respond to medical therapy alone.3 Cases that are resistant to medical therapy are treated with surgical intervention.10
The surgical management includes early PKP with lens removal in case of anterior chamber involvement (therapy-resistant hypopyon).2,3,15 An amniotic membrane graft can be used because it serves as a new basement membrane for corneal epithelial cells after eradication of the hyphae.16 Or, it can be used as a graft to stimulate epithelial healing. According to Behrens-Baumann et al.,15 a graft is recommended after PKP in resistant cases to give intracameral antifungals.
In our opinion, we needed to reoperate because of the complete cessation of steroids with major exacerbation and because the initial graft was too small. Now, we believe that 11.0 to 12.0 mm grafts with multiple single sutures are the right way to treat if the entire cornea and the anterior chamber are affected.
However, in some cases, even corneal surgery will not restore vision and patients will be blind or even require enucleation of the globe. Therefore, early diagnosis coupled with appropriate treatment is critical to recover from Fusarium keratitis. We can achieve that and improve the outcomes with the following measures: intrastromal injection of voriconazole, removal of the graft epithelium, repeated washing of the anterior chamber with medications every 2 days, and confocal microscopy for early diagnosis and recurrence detection.12
In conclusion, this case underlines the role of confocal microscopy in early clinical diagnosis of the F solani organism, the necessity of starting the treatment with surgical intervention as soon as possible with using a large graft, and intrastromal antifungal injection in a case that does not response to intensive medical treatment. Early topical steroids are to be avoided. With F solani keratitis, the patient is threatened by the risk for enucleation, which was prevented in this patient by intensive medical and surgical care.
None of the authors has a financial or proprietary interest in any material or method mentioned.
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