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Cornea / External Disease

CORNEA AND EXTERNAL DISEASE: MEDICAL AND SURGICAL ADVANCES

Introduction
Updates on the recent outbreaks of microbial keratitis were foremost among corneal presentations at the 2007 annual meeting of the American Academy of Ophthalmology (AAO). Other topics included medical approaches to common cornea and external diseases and new findings in surgical care, including limbal stem cell grafting, femtosecond laser cutting, and selective endothelial replacement.

Medical Care of the Cornea
Microbial Keratitis
During a joint symposium with the Contact Lens Association of Ophthalmologists, Dr. William Ehlers[1] presented an update on the Fusarium keratitis epidemic that began in 2005. Dr. Ehlers summarized the generally accepted features of keratomycosis, including its higher prevalence in warmer climates (it accounts for up to 35% of cases of microbial keratitis in the southern United States but only 1% of cases in the north). The proportion of cases of keratomycosis caused by Fusarium species also varies by region, again with most, at least prior to the contact lens-associated epidemic, occurring in the south. There are more than 20 million species of Fusarium, a filamentous, nonpigmented fungus, but Fusarium solani has typically been the most implicated and the most virulent in instances of keratomycosis in humans. Dr. Ehlers emphasized that human cases of keratomycosis appeared to be on the rise, even prior to the 2005 outbreak. Before the "epidemic," trauma, immunosuppression, debilitated ocular surface, and chronic topical steroid use were the predominant predisposing factors for an individual developing keratomycosis.

Fungus is often not suspected initially when ophthalmologists evaluate a patient with keratitis or corneal ulcer. Suspicion should be heightened, however, because early diagnosis is key to salvaging the eye and eventual resurrection of useful vision. The appearance of a gray-white infiltrate with feathery edges and so-called "satellite lesions" should make the ophthalmologist particularly suspicious of keratomycosis. Confocal microscopy can be extremely helpful in demonstrating, through noninvasive techniques, frank fungal elements. Harvesting of material for slide preparation and culture is essential, with request for "special" stains, such as giemsa, PAS, methamine silver, and calciflor white techniques for demonstrating the fungal elements. Cultures should be established not only on Sabouraud's medium but also on blood agar plates held at room temperature.

In regard to the Fusarium epidemic beginning in Hong Kong and Singapore in 2005, with strong association in contact lens wearers using ReNu with MoistureLoc (Bausch & Lomb, Rochester, New York) for their lens care, Dr. Ehlers indicated that by April 9, 2006, the Centers for Disease Control and Prevention (CDC) had a list of 109 suspected cases in 17 states, 93 cases occurring in soft contact lens wearers. Bausch & Lomb withdrew ReNu with MoistureLoc permanently from the worldwide market in May 2006, and the company reported their hypothesis of the proposed mechanism of infection at the Congress of the Asia-Pacific Academy of Ophthalmology in Singapore in June of that year. The company estimated that corneal infection had occurred in approximately 1 in 16,667 ReNu with MoistureLoc users. Extensive investigations by Bausch & Lomb disclosed no contamination at production plants in Greenville, South Carolina, or in Milan, Italy, or evidence of product contamination, tampering, or counterfeiting, as well as no loss of efficacy at high temperature or humidity. All lots tested from both plants were highly effective in vitro. Controlled, monitored studies in humans using the ReNu with MoistureLoc products demonstrated unequivocally that it was safe and effective when used as directed. Patient noncompliance habits were ultimately believed to contribute to the reduction in disinfectant efficacy. These habits were identified as:

- Irregular cleaning of contact lens cases,
- Not replacing lens cases regularly,
- Poor hygiene with respect to bottle caps,
- Leaving bottles and lens cases open,
- Poor hand washing and incomplete rinsing of hands,
- No rinsing of lens, and
- Topping off solution in contact lens cases.

Fusarium species were shown to be capable of adapting to polymer films on surfaces, and the product design with its "snap cap" was shown to be prone to polymer film formation. It was concluded that the high polymer content in ReNu with MoistureLoc combined with poor patient hygiene and habits reduced the margin of safety for the use of this product, hence its recall from the market. This saga has once again refocused our attention on the critical importance of correct contact lens care.

On the heels of the Fusarium outbreak, a rise in Acanthamoeba corneal infections has been observed -- and these infections also have a strong association with contact lens wear and poor contact lens hygiene habits. De Freitas and associates[2] reported their findings of an analysis of corneal scrapings and contact lens cultures. The recovery of 175 Acanthamoeba isolates translated to an incidence rate of 15.9 Acanthamoeba-associated corneal infections per year. Nguyen and colleagues[3] reported on similarly poor outcomes in patients with Acanthamoeba keratitis as in those with Fusarium keratitis and a similar need for corneal transplantation in an effort to save the eye. Five patients with deep stromal ulcers due to Acanthamoeba keratitis were treated with intensive antiparasitic medication followed by penetrating keratoplasty during the acute infectious phase of the disease because of progressive keratopathy and intractable patient pain. The grafts were large enough to be certain that the margins of excision encompassed all areas of active infection. The surgery proved to be not only therapeutic, in that the infection was cured through the surgery, but the visual outcomes were also surprisingly good, ranging from 20/20 to 20/40 (average follow up, 53 weeks).

Bacterial keratitis remains the number one cause of microbial keratitis, and Wagoner and colleagues[4] reported on their analysis of 78 and 103 consecutive patients admitted in 1995 and in 2005, respectively, to a tertiary eye care center for bacterial keratitis. They demonstrated that significant improvements occurred between those 2 cohorts of patients, analyzed in the percentage of eyes achieving a microbiological cure with medical therapy and in those obtaining a final visual acuity of equal to or better than 20/40. They attributed this improvement to a standardization of inpatient microbiological therapeutic regimens and increased emphasis on adjunctive anti-inflammatory therapy. Rather than withhold topical corticosteroid therapy, practitioners employed it as soon as they were confident that the antimicrobial therapy was appropriate and was beginning to control the infection.

Ocular Rosacea
Zaidman[5] reported on the efficacy of once-daily oral azithromycin in the treatment of children with ocular rosacea. Two children, aged 3 and 8 years, had histories of recurrent chalazia, chronic meibomian gland dysfunction and blepharitis, corneal neovascularization, and recurrent phlectenular keratitis. They were diagnosed with pediatric ocular rosacea, and systemic azithromycin suspension was prescribed (15 mg/kg/day for 8 weeks), along with 10 days of topical therapy with a corticosteroid-antibiotic suspension. The author reported that the acute keratitis resolved rapidly, with no recurrence of the disease after the cessation of the topical and systemic program.

Corneal Neovascularization
Corneal neovascularization therapy with the vascular endothelial growth factor inhibitor bevacizumab continues to be a hot topic. Bahar[6] described the regression of corneal vessels, documented by serial photography graded by 2 masked observers, after the administration of subconjunctival bevacizumab in 10 patients with corneal neovascularization. The average follow-up time was 3.5 months. No adverse events were reported, and 7 of the 10 patients demonstrated at least partial regression of the vessels. The authors concluded that subconjunctival bevacizumab is well tolerated and is associated with at least partial regression of corneal neovascularization.

Topical bevacizumab therapy for corneal neovascularization was evaluated by DeStafeno and Kim.[7] Product concentration of 10 mg/mL was applied 4 times daily for 25 days in 2 patients with corneal neovascularization. The authors reported a "marked" reduction in superficial and deep corneal neovascularization with no adverse events noted.

External Disease
Anzaar and colleagues[8] reported on their experience with the use of systemic tacrolimus for patients with otherwise treatment-resistant atopic keratoconjunctivitis. They described 3 patients who had failed multiple topical and systemic treatment programs. All 3 patients had a dramatic improvement in the signs and symptoms of atopic keratoconjunctivitis, and all had associated improved visual acuity. This report adds to a growing body of evidence that systemic calcineurin and inhibitor therapy can be, even in instances where topical therapy with calcineurin inhibitors has failed, effective not only for the ocular manifestations of atopic keratoconjunctivitis but for the associated eczema as well.

Yadav and associates[9] reported on the efficacy of 5% povidone iodine as a lid scrub in the care of patients with blepharitis. The authors employed lid hygiene 2 times per day with a cotton tipped applicator dipped in 5% povidone iodine solution in 100 patients. Slit lamp examinations were performed for 1 week thereafter, monitoring for crusting, scaling, lid margin erythema, edema, and discharge, all graded on a scale of 0 to 3+. On day 7, the scales had been reduced in 98% of patients, erythema and edema had been reduced in 93.4%, and discharge reduced in 92.7%. The authors concluded that 5% povidone iodine is safe for ocular use, is well-tolerated, and is more effective than shampoo and lid scrubs for patients with chronic blepharitis.

Corneal Collagen Crosslinking
A relatively new and novel strategy for treating patients with keratoconus received more exposure at the AAO meeting. Specifically, corneal collagen crosslinking with riboflavin and ultraviolet radiation was highlighted by 2 groups.[10,11] In a controlled case series,[10] 16 eyes with keratoconus underwent corneal crosslinking using riboflavin and ultraviolet light (395 nm). Improvements in vision were recorded as early as 1 month following the treatment, and the treatment was associated with a cessation of keratoconus progression in all patients. No one lost vision, 8 patients maintained vision, and 3 gained 1 line, with 1 patient gaining 2 lines of vision. An expansion of an earlier report[11] showed improvement in the results of 38 eyes of 19 patients 6 months following this procedure. The maximum keratometry reading decreased by 1.75 diopters, the best corrected visual acuity improved by 0.04 in the fellow untreated eye, the maximum keratometry reading increased by .24 diopters, and vision decreased by .02. The authors concluded that corneal collagen crosslinking appears to be a safe procedure that stops the progression of keratoconus and even reduces to some degree the steepness of the corneal curvature.

Kymionis and associates[12] evaluated corneal tissue alterations after corneal crosslinking with riboflavin and ultraviolet radiation in corneal ectatic disorders, specifically patients with keratoconus or post-LASIK corneal ectasia. The patients were evaluated monthly for 6 months following the procedure, and anterior cornea stromal was found to be depleted of keratocyte nuclei following therapy and at the first 3 monthly visits. The collagen fibers in the superior stromal were distributed unevenly, taking a "net-like" appearance, with recolonization of the superior corneal stroma demonstrable over months 4, 5, and 6 postprocedure. The authors concluded that corneal collagen crosslinking induces significant alterations in corneal morphology at the microscopic level.

Surgical Care of the Cornea
Femtosecond Laser
Femtosecond laser cutting of corneal tissue appears to be ready for "prime time," with the experimental and preclinical and early clinical studies having demonstrated its effectiveness and safety. Daya and colleagues[13] described the outcomes of penetrating keratoplasty performed using the IntraLase femtosecond laser (IntraLase Corp., Irvine, California) to produce formed cuts, called tongue-and-groove geometric patterns, on both donor and host cornea in 5 eyes of patients with Fuchs' endothelial dystrophy (n=2), keratoconus (n=2), and pseudophakic bullous keratopathy (n=1). Six months following surgery, 80% of the patients had best corrected visual acuity of equal to or better than 20/40, with a mean endothelial cell count of 2890 and a spherical equivalent of -1.6 diopters with keratometric cylinder of 4.6 diopters.

Holzer and colleagues[14] analyzed the endothelial cell density following femtosecond laser-assisted penetrating keratoplasty in 11 eyes. Endothelial cell counts of the corneal donor buttons were measured both preoperatively and postoperatively at 12 and 24 months by specula microscopy. The preoperative cell counts on the corneal buttons ranged from 2300 to 2750 cells/mm2. All transplants were clear 24 months after surgery, with improved visual acuity, and with endothelial cell counts ranging from 1350 to 2100 cells/mm2 (median cell loss 36%). The authors concluded that endothelial cell loss was similar to that of conventional keratoplasty.

Descemet-Stripping Automated Endothelial Keratoplasty
The other major advance in corneal surgery over the past 5 years has been Descemet-stripping automated endothelial keratoplasty (DSAEK). When successful, this technique results in much more rapid visual rehabilitation and lack of surgically induced astigmatism in patients who have endothelial pathology but otherwise normal corneas than earlier keratoplasty procedures. However, there is a steep learning curve for the procedure.

In an effort to assess predictors of good outcomes, Shamie and Terry[15] described 6-month outcomes in 97 eyes after DSAEK. Patients younger than age 60, patients with preoperative visual acuity of 20/40 or better, and patients with pachymetry readings of less than 700 microns were the most likely to have excellent 6-month postoperative visual acuity. This group also reported on a subset of 4 eyes with unacceptable vision following endothelial keratoplasty. They were treated with replacement of the grafts, which resulted in good outcomes. The authors stated that "postendothelial keratoplasty surgery eyes with unacceptable vision thought to be due to poor interface quality can be treated by replacing the endothelial graft using a microkeratome-prepared donor tissue or by performing a full thickness penetrating keratoplasty."

Hall and Parker[16] sought to compare the differences in visual outcomes for 4 patients who underwent penetrating keratoplasty in one eye and DSAEK in the fellow eye. All 8 eyes achieved best corrected visual acuity with spectacles of 20/40 or better. The average time the best corrected visual acuity occurred was significantly sooner after DSAEK (2.5 months) compared with penetrating keratoplasty (10.1 months). All patients preferred vision in the eye that had DSAEK compared with vision in the eye that had penetrating keratoplasty.

Groat and associates[17] evaluated the outcomes of small-incision clear corneal DSAEK in 86 patients. Patients had a mean best corrected visual acuity of 20/40 three months postoperatively. There was a 23% decrease in donor endothelial cell count at 6 months postoperatively, and no change in the 6-month topographical astigmatism characteristics compared with preoperative astigmatism. The authors concluded that DSAEK has excellent and rapid improvement in vision with no change in astigmatism and only a moderate endothelial cell loss.

An increasing number of corneal surgeons are training to perform DSAEK because of the early favorable results. However, it should be noted that the learning curve for the technique is steep, and postoperative complications can and do occur. Still, it appears that this surgical technique is likely to increasingly replace full-thickness penetrating keratoplasty for patients with corneal edema.

Limbal Stem Cell Grafting
Ocular surface reconstruction through limbal stem cell grafting continues to be an important corneal surgical technique in the care of patients with ocular surface disease resulting in limbal stem cell deficiency. Like DSAEK, it is technically challenging, and when the graft is an allograft instead of an autograft, the challenges of systemic immunosuppressive chemotherapy are added to the picture.

Arora and colleagues[18] described the outcome of limbal stem cell autografts in 77 patients with unilateral limbal stem cell deficiency, operated on between 1997 and 2006. Amniotic membrane grafting, sequential keratoplasty, and conjunctival surgery were employed. The authors reported an 80% success rate in ocular surface reconstruction with fornix formation and improved corneal clarity and reduced neovascularization at the 2-year follow-up period. This success rate is expected in a cohort of patients who receive autografts rather than allografts.

The situation can sometimes be additionally enhanced through the use of in vitro expansion of limbal epithelium from the noninjured eye of a patient with unilateral disease. Swarup and colleagues[19] described the use of this approach in 17 patients treated between 2001 and 2005. Chemical injury was the primary original insult to the injured eye. The mean reduction in "conjunctivalization" of the corneal surface was 1.27 quadrants, with 6 patients having stable ocular surface with less than 1 quadrant of peripheral conjunctivalization. Seven patients had partial success, with peripheral recurrence of the conjunctivalization, and 2 patients failed to have successful reconstruction of the ocular surface.

References
1- Ehlers WH. Fusarium keratitis. Program and abstracts of the American Academy of Ophthalmology 2007 Annual Meeting; November 10-13, 2007; New Orleans, Louisiana. Symposium 09.
2- de Freitas D, Ramos F, Foronda A, Zorat-Yu MC, Hofling-Lima AL. Ten years of Acanthamoeba keratitis in Brazil. Program and abstracts of the American Academy of Ophthalmology 2007 Annual Meeting; November 10-13, 2007; New Orleans, Louisiana. Poster 297.
3- Nguyen TH, Weisenthal RW, Florakis GJ. Early intervention with therapeutic penetrating keratoplasty in active Acanthamoeba keratitis. Program and abstracts of the American Academy of Ophthalmology 2007 Annual Meeting; November 10-13, 2007; New Orleans, Louisiana. Poster 313.
4- Wagoner, MD, Al-Shehri A, Jastaneiah S. Outcome of treatment of severe bacterial keratitis at a tertiary eye care center. Program and abstracts of the American Academy of Ophthalmology 2007 Annual Meeting; November 10-13, 2007; New Orleans, Louisiana. Poster 48.
5- Zaidman GW. Once daily oral azithromycin for the treatment of pediatric ocular rosacea. Program and abstracts of the American Academy of Ophthalmology 2007 Annual Meeting; November 10-13, 2007; New Orleans, Louisiana. Poster 282.
6- Bahar I, Kaiserman I, McAllum PJ, Rootman DS, Slomovic AR. Subconjunctival bevacizumab injection for corneal neovascularization. Program and abstracts of the American Academy of Ophthalmology 2007 Annual Meeting; November 10-13, 2007; New Orleans, Louisiana. Poster 281.
7- DeStafeno JJ, Kim K. Topical bevacizumab (Avastin) therapy for corneal neovascularization. Program and abstracts of the American Academy of Ophthalmology 2007 Annual Meeting; November 10-13, 2007; New Orleans, Louisiana. Poster 288.
8- Anzaar F, Bhat P, Gallagher MJ, Arif M, Farooqui A, Foster CS. Systemic tacrolimus therapy for resistant atopic keratojunctivitis. Program and abstracts of the American Academy of Ophthalmology 2007 Annual Meeting; November 10-13, 2007; New Orleans, Louisiana. Poster 294.
9- Yadav P, Sharmar P, Mohan H. Lid hygiene with povidone iodine 5% W/P: a new and effective 7 day modality in the treatment of blepharitis. Program and abstracts of the American Academy of Ophthalmology 2007 Annual Meeting; November 10-13, 2007; New Orleans, Louisiana. Poster 305.
10- Jankov MR, Zora IR, Kuljaca ZD. Corneal cross linking with riboflavin and UC radiation in patients with keratoconus: six months results. Program and abstracts of the American Academy of Ophthalmology 2007 Annual Meeting; November 10-13, 2007; New Orleans, Louisiana. Poster 40.
11- Coskunseven E, Balci O, Atun S, Arslan E, Jankov MR. Comparative study of corneal crosslinking with riboflavin and UV radiation in with patients with keratoconus: six months results. Program and abstracts of the American Academy of Ophthalmology 2007 Annual Meeting; November 10-13, 2007; New Orleans, Louisiana. Poster 39.
12- Kymionis GD, Diakonis DF, Bouzoukis DI, Portaliou D, Yoo SH, Pallikaris A. Confocal microscopy analysis after corneal cross linking. Program and abstracts of the American Academy of Ophthalmology 2007 Annual Meeting; November 10-13, 2007; New Orleans, Louisiana. Poster 287.
13- Daya SM, Khan SH, Hamada S, Espinosa-Lagana MM. Femtosecond laser penetrating keratoplasty using tongue and groove geometric patterns. Program and abstracts of the American Academy of Ophthalmology 2007 Annual Meeting; November 10-13, 2007; New Orleans, Louisiana. Poster 60.
14- Holzer MP, Sanchez MJ, Ehmer A, Naqadan F, Rabsilber TM, Auffarth GU. Endothelial cell count following femtosecond laser assisted penetrating keratoplasty. Program and abstracts of the American Academy of Ophthalmology 2007 Annual Meeting; November 10-13, 2007; New Orleans, Louisiana. Poster 66.
15- Shamie N, Terry MA, Chen ES, Saad HA, Friend D. Descemet-stripping automated endothelial keratoplasty: predictive factors for good visual acuity at six months. Program and abstracts of the American Academy of Ophthalmology 2007 Annual Meeting; November 10-13, 2007; New Orleans, Louisiana. Poster 289.
16- Hall TA, Parker JS. Vision after fellow eye Descemet-stripping automated endothelial keratoplasty preferred over vision after penetrating keratoplasty. Program and abstracts of the American Academy of Ophthalmology 2007 Annual Meeting; November 10-13, 2007; New Orleans, Louisiana. Poster 67.
17- Groat BJ, Ying MS, Vroman DT. Outcomes of small-incision clear corneal Descemet-stripping automated endothelial keratoplasty. Program and abstracts of the American Academy of Ophthalmology 2007 Annual Meeting; November 10-13, 2007; New Orleans, Louisiana. Poster 43.
18- Arora R, Jain T, Raina UK, Ghosh B. Outcome of limbal autograft transplant with other modalities in the management of disorders with moderate to severe limbal deficiency. Program and abstracts of the American Academy of Ophthalmology 2007 Annual Meeting; November 10-13, 2007; New Orleans, Louisiana. Poster 56.
19- Swarup R, Sangwan VS, Vemuganti GK, Fatima A, Rao GN. Outcome of ipsilateral ex vivo cultivated limbal epithelial transplantation for partial limbal stem cell deficiency. Program and abstracts of the American Academy of Ophthalmology 2007 Annual Meeting; November 10-13, 2007; New Orleans, Louisiana. Poster 303.

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