Sonal S. Tuli

Fungal keratitis: emerging trends and treatment outcomes.

Purpose. To review the trends, risk factors, causative organisms, treatment, and outcomes of fungal keratitis at the authors’ institution. Methods. A retrospective review of the records of consecutive patients diagnosed with fungal keratitis at the authors’ institution from January 1999 to June 2006. Results. Eighty-four patients were diagnosed with fungal keratitis during this period. The average age of the patients was 48 years, and 64% were male. Until 2004, trauma (51%) and contact lens use (40%) were the major risk factors. After 2005, contact lens use (52%) surpassed trauma as the most common risk factor (29%). The percentage of fungal ulcers caused by nontherapeutic contact lenses increased from 21% between 1999 and 2001 to 32% between 2002 and 2004 and to 45% in 2005 and 2006. Eighty-six percent of cultured organisms were filamentous. Fusarium (41%) was the most commonly isolated genus, followed by Candida (14%), Curvularia (12%), and Aspergillus (12%). Visual acuity was worse than 20/200 in 56% of patients at presentation. Final visual acuity was 20/40 or better in 70% of patients treated with medication alone and 16% of patients requiring therapeutic keratoplasty. Surgical intervention in the acute phase was necessary in 23% of patients. Seventy-four percent of medically treated patients had dual topical antifungal therapy. Natamycin 5% and amphotericin B 0.15% were the most commonly used drugs. Conclusions. Contact lenses are a major risk factor for fungal keratitis. The incidence of contact lens–related fungal keratitis was increasing even before the Fusarium outbreak in 2005 and 2006. Good visual outcomes can be achieved by aggressive dual topical antifungal therapy.

Clinical and microbiological characteristics of fungal keratitis in the United States, 2001-2007: a multicenter study.

OBJECTIVE To study the epidemiology, clinical observations, and microbiologic characteristics of fungal keratitis at tertiary eye care centers in the United States. DESIGN Retrospective multicenter case series. PARTICIPANTS Fungal keratitis cases presenting to participating tertiary eye care centers. METHODS Charts were reviewed for all fungal keratitis cases confirmed by culture, histology, or confocal microscopy between January 1, 2001, and December 31, 2007, at 11 tertiary clinical sites in the United States. MAIN OUTCOME MEASURES Frequency of potential predisposing factors and associations between these factors and fungal species. RESULTS A total of 733 cases of fungal keratitis were identified. Most cases were confirmed by culture from corneal scraping (n = 693) or biopsies (n = 19); 16 cases were diagnosed by microscopic examination of corneal scraping alone; and 5 cases were diagnosed by confocal microscopy alone. Some 268 of 733 cases (37%) were associated with refractive contact lens wear, 180 of 733 cases (25%) were associated with ocular trauma, and 209 of 733 cases (29%) were associated with ocular surface disease. No predisposing factor was identified in 76 cases (10%). Filamentous fungi were identified in 141 of 180 ocular trauma cases (78%) and in 231 of 268 refractive contact lens-associated cases (86%). Yeast was the causative organism in 111 of 209 cases (53%) associated with ocular surface disease. Yeast accounted for few cases of fungal keratitis associated with refractive contact-lens wear (20 cases), therapeutic contact-lens wear (11 cases), or ocular trauma (21 cases). Surgical intervention was undertaken in 26% of cases and was most frequently performed for fungal keratitis associated with ocular surface disease (44%). Surgical intervention was more likely in cases associated with filamentous fungi (P = 0.03). Among contact lens wearers, delay in diagnosis of 2 or more weeks increased the likelihood of surgery (age-adjusted odds ratio = 2.2; 95% confidence interval, 1.2-4.2). CONCLUSIONS Trauma, contact lens wear, and ocular surface disease predispose patients to developing fungal keratitis. Filamentous fungi are most frequently the causative organism for fungal keratitis associated with trauma or contact lens wear, whereas yeast is most frequently the causative organism in patients with ocular surface disease. Delay in diagnosis increases the likelihood of surgical intervention for contact lens-associated fungal keratitis.

Trends in Fungal Keratitis in the United States, 2001 to 2007

OBJECTIVE Fungal keratitis is a serious ocular infection that is considered to be rare among contact lens wearers. The recent Fusarium keratitis outbreak raised questions regarding the background rate of Fusarium-related keratitis and other fungal keratitis in this population. DESIGN Retrospective, multicenter case series. PARTICIPANTS Six hundred ninety-five cases of fungal keratitis cases who presented to 1 of 10 tertiary medical centers from 2001 to 2007. METHODS Ten tertiary care centers in the United States performed a retrospective review of culture-positive fungal keratitis cases at their centers between January 2001 and December 2007. Cases were identified using microbiology, pathology, and/or confocal microscopy records. Information was collected on contact lens status, method of diagnosis, and organism(s) identified. The quarterly number of cases by contact lens status was calculated and Poisson regression was used to evaluate presence of trends. The Johns Hopkins Medicine Institutional Review Board (IRB) and the IRBs at each participating center approved the research. MAIN OUTCOME MEASURES Quarterly number of fungal keratitis cases and fungal species. RESULTS We identified 695 fungal keratitis cases; 283 involved the use of contact lenses. The quarterly number of Fusarium cases increased among contact lens wearers (CLWs) during the period that ReNu with MoistureLoc (Bausch & Lomb, Rochester, NY) was on the market, but returned to prior levels after withdrawal of the product from the market. The quarterly frequency of other filamentous fungi cases showed a statistically significant increase among CLWs comparing October 2004 through June 2006 with July 2006 through December 2007 with January 2001 through September 2004 (P < 0.0001). CONCLUSIONS The quarterly number of Fusarium fungal keratitis cases among CLWs returned to pre-Renu with Moistureloc levels after removal of the product from the market. However, the number of other filamentous fungal keratitis cases, although small, seems to have increased among refractive CLWs. Reasons for these apparent increases are unclear.

Growth factor, cytokine and protease interactions during corneal wound healing.

Healing of corneal injuries is an exceptionally complex process involving the integrated actions of multiple growth factors, cytokines, and proteases produced by epithelial cells, stromal keratocytes, inflammatory cells, and lacrimal gland cells. Following corneal injury, basal epithelial cells migrate and proliferate in response to chemotactic cytokines and mitogenic growth factors, including epidermal growth factor and keratinocyte growth factor. Simultaneously, keratocytes adjacent to the injured area undergo apoptosis under the Fas/Fas ligand system, while more distant keratocytes transform into activated fibroblasts and migrate into the wound, where they begin synthesizing new extracellular matrix components that form the scar tissue under the dominant influence of the TGFb/ CTGF system. Epithelial cells and activated stromal fibroblasts also secrete growth factors and cytokines that have paracrine and autocrine functions. Corneal repair proceeds for the next several weeks to months, during which time the gene expression profile slowly returns to the pre-injury pattern and the provisional scar matrix slowly remodels by actions of matrix metalloproteinases. While minor epithelial injuries heal by regeneration of normal architecture, large stromal injuries heal by repair with irregular scar tissue that impairs the optical properties of the cornea.Also, if the integrated regulation of the wound healing process is interrupted at any point, the wound fails to heal properly and a corneal ulcer develops. Better understanding of the cellular and molecular changes that occur during repair of corneal wounds will provide the opportunity to design agents that selectively modulate key phases of corneal wound healing, resulting in scars that more closely resemble normal corneal architecture.

Immunohistochemical localization of EGF, TGF-alpha, TGF-beta, and their receptors in rat corneas during healing of excimer laser ablation.

Purpose: Members of the epidermal growth factor (EGF) and transforming growth factor beta (TGF-β) families of growth factors and receptors are known to regulate key aspects of corneal wound healing, including epithelial migration and scar formation. To further understand their roles, mRNA levels were measured and proteins were immunolocalized in rat corneas at multiple time points during healing of excimer laser ablation injury. Methods: Excimer laser photoablation was performed to a depth of 50 μm on rat corneas. Levels of mRNAs for EGF, TGF-α, TGF-β isoforms 1, 2, and 3, and their receptors (EGF-R and TGFβ-IIR) were measured by quantitative RT-PCR on days 0, 1.5, 7, 21, 42, and 91 after ablation. Immunohistochemical localization of the growth factors and their receptors was performed on days 0, 7, and 21 in corneal sections. Results: Levels of EGF mRNA remained stable in rat corneas after ablation (68 ± 12 copies/cell, mean ± SD), whereas levels of TGF-α mRNA progressively increased sixfold to a maximum at day 42 (300 copies/cell) then slightly decreased on day 91. Levels of EGF-R mRNA rapidly increased 60-fold on day 7 compared with day 0 (571 vs. 9 copies/cell) then decreased sixfold above baseline at day 91. Levels of TGF-β1 mRNA remained stable (36 ± 10 copies/cell), whereas levels of TGF-β2 and TGF-β3 mRNAs peaked on day 21 (300-fold and 25-fold increase) and remained elevated through day 91. Levels of TGFβ-IIR mRNA showed a similar pattern. Immunostaining of all the growth factors and receptors was primarily in basal layers of epithelial cells in uninjured cornea and during healing. Intensity of immunostaining for TGF-β1, TGFβ-IR, and TGFβ-IIR increased appreciably in the basal epithelial layers after ablation. Conclusions: Levels of mRNAs for several key members of the EGF and TGF-β systems increase during corneal wound healing. In addition, the proteins are primarily localized in basal layers of epithelial cells, which suggest these cells are active in synthesizing autocrine and paracrine growth factors that modulate corneal wound healing.

Science and strategy for preventing and managing corneal ulceration.

ABSTRACT Corneal ulcers can cause significant loss of vision from scarring and astigmatism, but rapid management can limit the destruction and improve outcomes. Infectious ulcers usually resolve with antimicrobial treatment. Noninfectious ulcers, however, present a diagnostic and therapeutic challenge. They can often be resolved by eliminating toxic medications and providing surface support with lubrication and collagenase inhibitors, but resistant ulcers may need more aggressive therapy with bandage contact lenses, tarsorrhaphy, or autologous serum. Ulcers impending perforation require urgent surgical management (e.g., tissue glue, conjunctival flaps, or keratoplasty). Topical steroids are useful when the ulceration is secondary to inflammatory mediators, but they are contraindicated in corneal melts with minimal inflammation, such as those associated with Sjogren syndrome. Systemic immunomodulation is required in addition to topical therapy in the presence of autoimmune disease. Understanding of the pathological processes that occur in different types of corneal ulcers is essential to formulation of a logical and effective treatment plan. Newer, more targeted treatment modalities may offer treatment options that have greater efficacy and fewer adverse effects.

Delayed Ectasia Following LASIK With No Risk Factors: Is a 300-µm Stromal Bed Enough?

PURPOSE To report a case of ectasia occurring > 4 years following LASIK with no risk factors and a residual stromal bed > 300 microm. METHODS A 33-year-old woman presented 4 years after LASIK with mild blurring in the left eye. Uncorrected visual acuity (UCVA) had been 20/20 in both eyes previously. RESULTS Uncorrected visual acuity was 20/20 and 20/40 in the right and left eyes, respectively. Best spectacle-corrected visual acuity (BSCVA) was 20/20 with -0.75 +2.25 x 70 degrees refraction in the left eye, which matched topography. Preoperative corneal thickness was 595 microm, and topography showed no risk factors preoperatively or immediately postoperatively. Calculated residual stromal bed was 342 microm and measured 400 microm with ultrasound microscopy. One year postoperatively, UCVA decreased to 20/400, and BSCVA decreased to 20/60 with refraction of -4.50 +5.00 x 90 degrees. The patient was intolerant of contact lens wear and is considering collagen cross-linking, Intacs, or corneal transplantation. CONCLUSIONS Ectasia can occur more than 4 years after LASIK. Its etiology is unknown and management is challenging.

Fungal keratitis and contact lenses: An old enemy unrecognized or a new nemesis on the block?

Purpose. To review studies of fungal keratitis related to contact lenses and determine whether the recent insurgence is a new phenomenon or an exacerbation of an ongoing trend. Methods. A review of the recent literature on contact lens–related fungal ulcers and a comparison to older studies. Results. The incidence of fungal keratitis associated with contact lenses increased from 5% in the 1980s to between 10% and 25% in the 1990s and was noted to be 44% in Florida at the turn of the century. The most recent study from Florida showed that the incidence had increased from 29% in the late 1990s to 52% in the early 2000s, even before the Fusarium keratitis epidemic in 2004 and 2005. This increase mainly represented an increase in the number related to nontherapeutic contact lenses. Conclusions. Contact lens–related fungal keratitis was relatively rare 20 years ago. However, the incidence has progressively increased since then. Contact lens–related fungal ulcers had become more common even before the recent Fusarium keratitis epidemic. This change may be related to changing contact lens care habits and younger patients being fitted with contact lenses.

Five-year outcomes of eyes with glaucoma drainage device and penetrating keratoplasty.

PurposeTo investigate intraocular pressure (IOP) control and corneal graft survival rates in eyes with glaucoma drainage device (GDD) implantation and penetrating keratoplasty (PK) and 5 years of follow-up data. DesignRetrospective review. MethodsWe performed a review of records of all patients who underwent both GDD placement and PK at our institution between January 1, 1988 and December 31, 2003. Twenty-eight eyes of 27 patients were studied. Glaucoma outcome was assessed by postoperative IOP, number of glaucoma medications, and need for further glaucoma surgery. Corneal grafts were assessed for clarity. ResultsAll eyes had GDD placement in the anterior chamber. The mean pre-GDD IOP was 28.8±10.3 mm Hg on a mean of 2.6±0.8 glaucoma medications. At 5-year follow-up, the mean IOP was 13.0±5.9 mm Hg on a mean of 0.9±1.0 glaucoma medications. GDD implantation successfully controlled glaucoma in 96%, 86%, 79%, 75%, and 71% of eyes at 1, 2, 3, 4, and 5 years, respectively. Grafts remained clear in 96%, 82%, 75%, 57%, and 54% of eyes at 1, 2, 3, 4, and 5 years, respectively. Failure of glaucoma outcome or graft survival was associated with prior intraocular surgeries. ConclusionsOur data suggests that GDD placement can provide glaucoma control in a high percentage (71%) of eyes with PK even at 5 years. Furthermore, the success of PK in eyes with GDD remains reasonable (54%) at 5 years. IOP control and graft survival rates are comparable with earlier published studies with shorter follow-up or tube placement in the vitreous cavity.

Reactivation of herpes zoster keratitis in an adult after varicella zoster vaccination.

Purpose: In this study, the case of a patient who presented with reactivation of herpes zoster (HZ) keratitis and worsening of neurotrophic keratopathy, keratouveitis, and keratoconjunctivitis sicca after vaccination with live attenuated HZ vaccine (Zostavax) is described. Method: This is a retrospective case review. Results: A 63-year-old man, with a history of HZ keratouveitis and neurotrophic keratopathy that had been quiescent for 3.5 years off medication, presented with keratouveitis 2 weeks after Zostavax administration. Oral acyclovir and topical prednisolone acetate and cyclopentolate were started, with subsequent improvement in inflammation and visual acuity. However, the patient was unable to be tapered completely off the steroids. Conclusions: HZ keratouveitis is the result of cell-mediated immunity (CMI) directed toward viral antigens within the eye. The live attenuated HZ vaccine, Zostavax, boosts the recipient’s CMI to prevent reactivation of HZ. However, patients with a history of HZ keratitis may have persistent viral antigens in their corneas and can develop recurrence of keratouveitis because of the vaccine-induced increase in CMI. Vaccination should be undertaken with caution in patients with a history of HZ ophthalmicus.