CORNEA AND REFRACTIVE SURGERY
From the 2008 Annual Meeting, New Trends and Advances in Ophthalmology, presented by the Washington Academy of Eye
Physicians and Surgeons, Seattle, WA
Stephen D. McLeod, MD, Professor and Chair, Department of Ophthalmology, University of California, San Francisco,
School of Medicine
Educational Objectives
| The goals of this activity are to improve the management of infectious keratitis and to improve outcomes after
refractive surgery and corneal transplantation. After hearing and assimilating this program, the clinician will be
better able to:
|
 | 1. Diagnose and treat patients with infectious keratitis.
|
| 2. Identify appropriate patients for refractive surgery.
|
| 3. Educate patients about the risks associated with refractive surgery.
|
| 4. Use appropriate pharmacologic agents to improve outcomes after corneal transplantation.
|
| 5. Discuss the role of ABO HLA matching between donor corneas and recipients.
|
Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts
of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health
care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. McLeod
is a shareholder of and receives research support from Visiogen, Inc. The planning committee reported nothing to disclose.
Acknowledgments
Dr. McLeod was recorded at New Trends and Advances in Ophthalmology, presented by the Washington Academy of
Eye Physicians and Surgeons, held March 27-28, 2008, in Seattle, WA. The Audio-Digest Foundation thanks Dr.
McLeod and the Washington Academy of Eye Physicians and Surgeons for their cooperation in the production of this
program.
| CLINICAL DECISION MAKING IN INFECTIOUS KERATITIS
|
| Case: woman, 46 yr of age, with history of non-Hodgkin’s lymphoma, wears soft contact lenses; presentation includes
red eye, mild decrease in vision (20/30), and decreased corneal sensation; clinical decisions—whether and
how to culture; when to initiate treatment and with which agent; whether and how to use corticosteroids
|
| Culture vs empiric therapy: 1992 survey showed ≈50% of corneal ulcers sampled for Gram stain or culture; samples
most often taken with swab and placed in transport medium; decision to culture depends on severity of ulcer
and clinical suspicion; typical contact lens-related ulcers often treated empirically (\>90% of community-acquired
bacterial ulcers respond to second-generation fluoroquinolones); practical issues—cost and limited lifespan of culture
plates; low frequency of infectious cases; prerequisites for empiric therapy—high probability of response to initial
antibiotic (treatment failure leads to increased necrotic destruction and worse visual outcomes); low probability
of atypical nonbacterial organisms (eg, Fusarium)
|
| Culture techniques: study (from south India) compared direct inoculation of culture plates with “swab and send”
technique using Amies transport medium without charcoal (medium also allows preparation of smears); of 100
consecutive cases of presumed infectious keratitis, pathogens identified (using Gram stain and potassium hydroxide
test) in 69 eyes; in 26 eyes, etiology bacterial, in 43 eyes, etiology fungal; results—no differences seen between
techniques (direct plating or use of Amies transport medium) or timing of transfer to plates (4 hr or 24 hr);
conclusions—use of Amies medium reasonable alternative to direct plating; larger prospective study recommended
to assess efficacy in United States population
|
| Fluoroquinolones: first-line therapy, but rate of resistance increasing (varies with geographic area); in United
States, increases in resistance seen in Staphylococcus aureus; second-generation agents—less active against gram-
positive organisms (eg, Streptococcus pneumoniae) and penicillin-resistant organisms; fourth-generation agents—less
active against gram-negative organisms (eg, Pseudomonas), but increased penetration may compensate (also, increasing
concentration helps); combination therapy—combining second- and fourth-generation agents does not provide
additional benefit; other studies—in vivo studies and clinical evaluations show moxifloxacin similar to
ciprofloxacin for activity against Pseudomonas, and similar to vancomycin for activity against methicillin-resistant S
aureus (MRSA; nevertheless, treatment failures have occurred); MRSA isolates with double mutations have high
level of resistance to fourth-generation agents
|
| Corticosteroids: controversy—corticosteroids control infection and scarring but increase risk for necrosis; infectious
keratitis—immune-mediated corneal damage leads to necrosis and degradation of organized collagen; angiogenesis
and resulting corneal neovascularization increase risk for graft rejection and other poor outcomes;
prevalence of use—≈70% of corneal disease specialists use corticosteroids in selected patients
|
| Clinical trial: pilot study randomized 42 patients with infectious keratitis to receive corticosteroids or placebo;
results—corticosteroid treatment associated with mild improvements (not statistically significant) in visual acuity,
degree of infiltrate and scarring, and reepithelialization at 3 wk and 3 mo; adverse events—2 perforations, one
case of elevated intraocular pressure (IOP), and one nonhealing ulcer occurred in placebo group; no adverse
events occurred in corticosteroid group; although poorly powered to detect infrequent adverse events, results encouraging;
larger trial—enrollment in progress
|
| Return to case: culture recommended because of atypical presentation; culture results important for directing therapy;
patient previously treated empirically with valacyclovir, but culture identified pathogen as fungal; patient responded
to antifungal therapy
|
| PATIENT SELECTION FOR LASIK
|
| Factors that increase risk: Food and Drug Administration (FDA) Web site lists blepharitis, large pupils, thin corneas,
dry eyes, and previous surgery as risk factors for developing complications after laser in situ keratomileusis
(LASIK); autoimmune diseases considered contraindication; most evidence comes from trials involving photorefractive
keratectomy (PRK); noninfectious ulcers reported in patients with systemic lupus erythematosus (SLE);
concern extended to all autoimmune diseases that increase risk for peripheral ulcerative keratitis (eg, rheumatoid arthritis
[especially problematic due to dry eyes], Wegener’s granulomatosis, Churg-Strauss syndrome, relapsing
polychondritis, and polyarteritis nodosa)
|
| Evidence: Cabo-Soriano et al—looked at 275 eyes in 141 patients; conditions included well-controlled autoimmune
disorders of connective tissue, psoriasis, ulcerative colitis, Crohn’s disease, diabetes, and keloid formation; 29 patients
required systemic immunosuppressive therapy to control disease; compared to healthy controls, patients with
risk factors had no difference in complication rates and only slightly worse refractive outcomes; Smith and
Maloney—smaller study looked at LASIK among patients with stable autoimmune diseases (eg, SLE, rheumatoid
arthritis, psoriatic arthritis, scleroderma, inflammatory bowel disease) without evidence of ocular disease; no complications
related to poor healing or epithelial disease observed
|
| Informed consent: in studies, use of LASIK in patients with well-controlled autoimmune disorders, without history
of ocular involvement, shown to have good results; however, clinical use in this group of patients may have
medicolegal repercussions, since prescribing information lists this as a contraindicated population; patient education
and informed consent important
|
| Rheumatoid arthritis: dry eyes increase risk for ocular problems after LASIK (highest risk for postoperative complications);
speaker avoids LASIK in these patients
|
| Herpes simplex virus (HSV): UV irradiation stimulates recurrence; rabbit studies show PRK and LASIK associated
with increase in positive cultures and shedding; prophylactic use of acyclovir attenuates recurrence; phototherapeutic
keratectomy (PTK)—3 cases of recurrent herpetic keratouveitis occurred during FDA trials of PTK;
LASIK—case reports suggest prophylaxis with acyclovir effective, but studies poorly powered to detect infrequent
events; possible occurrence of serious adverse events (eg, perforation) associated with aggressive HSV reactivation;
speaker generally avoids treatment with excimer laser in patients with history of ocular HSV
|
| Glaucoma: IOP measurements—concern about accuracy of measurements after LASIK or PRK (corneal thinning
may lead to underestimation of IOP); accumulation of interlamellar fluid—in setting of LASIK flap, fluid accumulation
and inflammation resembles diffuse lamellar keratitis (DLK); treatment with corticosteroids (appropriate for
managing DLK) increases IOP and leads to additional transudation into interlamellar space; clinical picture may
prompt second course of corticosteroids, leading to further exacerbation; intralamellar fluid beneath LASIK flap
artificially lowers IOP measurement; unrecognized complication may lead to loss of vision; speaker’s
recommendations—consider PRK over LASIK for patients at risk for glaucoma; take corneal thinning into account
when measuring IOP; discuss risks and benefits with patient and obtain informed consent
|
| Uveitis: trauma to cornea may initiate inflammatory cascade and stimulate recurrence of uveitis; inflammation impairs
function of endothelial pump; compromised pump leads to accumulation of intralamellar fluid or isolated edema of
LASIK flap and increases risk for complications; surgical options—consider surface procedure over lamellar procedure
|
| Forme fruste keratoconus: corneal rigidity—unpredictable changes associated with LASIK and PRK procedures;
large variation in baseline rigidity among individuals; baseline corneal thickness—300 µm of stress-bearing
cornea suggested (to maintain corneal stability); corneal stability also affected by intrinsic elastic properties; normal
corneas ≤250 µm have elastic properties similar to keratoconic corneas; PRK—study of patients with keratoconus
showed improvement in 4 of 5 eyes and no evidence of accelerated progression of disease; follow-up study
showed no exacerbations over 6 to 46 mo; another study showed improvement in 7 of 8 eyes and progression in 1
eye (unknown whether surgery induced progression); LASIK—risk for ectasia increases with high degree of myopia,
forme fruste keratoconus, and low residual stromal bed
|
| Pupil size: small treatment zones associated with higher degrees of glare and halo after surgery; some suggest effect
exacerbated by large pupil; newer instruments have larger treatment zones; more recent studies show risk for glare
and halo associated with smaller treatment zones, degree of preoperative myopia (strong association), and postoperative
residual refractive error, but not with size of pupil; quality of vision—includes glare, halo, and night vision;
associated with residual refractive error but not with pupil size; patient education and consent—discuss risks with all
patients; select patients appropriately to minimize risk for glare and halo
|
| PHARMACOLOGIC MANAGEMENT OF HIGH-RISK CORNEAL GRAFTS
|
| Corneal transplantation: low-risk grafts—regular graft with avascular bed; associated with 90% survival at 2 yr;
high-risk grafts—patient risk factors include young recipient age, number of previous grafts, history of anterior segment
surgery, and presence of synechiae or glaucoma; graft with large numbers of stromal vessels also increases
risk; studies show 2-yr rejection rate ≤45% (approaches rejection rate for solid organ transplantation)
|
| Corticosteroids: generally sufficient for regular grafts, but of limited value in preventing rejection of high-risk
grafts
|
| Cyclosporin A: widely used to suppress immunologic rejection after solid organ transplantation; associated with
renal and hepatic toxicity
|
| Topical: limited data suggest benefit (improved survival of graft); one study showed use of topical cyclosporine associated
with fewer episodes of rejection among high-risk grafts but no difference in 60-mo survival; efficacy—
low systemic activity may limit efficacy of topical formulation to repress immunologic response; toxicity—low
|
| Systemic: studies show conflicting results for graft survival; although data inconsistent, trends suggest improved graft
survival with daily oral doses of 3 to 5 mg/kg; acceptable option for patients at high risk for rejection; adverse
effects—high rate (10%) warrants follow-up (especially blood pressure and kidney and liver function) among patients
on systemic therapy; effects include renal function abnormalities, hypertension, paresthesias, and hypertrichosis
(especially among children receiving repeat grafts)
|
| Tacrolimus: mechanism of action involves T-cell signaling (similar to action of cyclosporine); limited data on use
in humans; adverse effects similar to those associated with cyclosporine (may limit tolerance)
|
| HLA matching: has clear benefit in solid organ transplantation; use in corneal transplantation—normal cornea
has low expression of HLA class I and II antigens and few blood and lymphatic vessels (for ingress of systemic
markers and egress of antigens); Collaborative Corneal Transplantation Studies (CCTS)—found no benefit associated
with matching donor and recipient HLA A, B, or DR antigens, but did show benefit associated with ABO
matching (graft failure rate 31% vs 41% without matching); used serologic method for HLA typing (associated
with relatively low accuracy, especially for HLA-DR antigen); Corneal Transplant Follow-up Study (United
Kingdom)—polymerase chain reaction (PCR)-based method for HLA typing; increased mismatch at HLA-A and
HLA-B loci associated with increased risk for rejection (finding that increased match of HLA-DR locus increased
risk for rejection not replicated by subsequent studies); recent studies—consistently show survival benefit
associated with high degree of HLA matching (ie, 0-1 mismatches); increasing number of mismatches
associated with lower rates of graft survival; conclusions—CCTS led to misperceptions about benefit associated
with HLA matching, but growing body of data supports benefit; practice change recommended
|
Suggested Reading
Böhringer D et al: Matching of the minor histocompatibility antigen HLA-A1/H-Y may improve prognosis in corneal
transplantation. Transplantation 82:1037, 2006; Chen A et al: Does in vitro susceptibility predict clinical outcome
in bacterial keratitis? Am J Ophthalmol 145:409, 2008; Cobo-Soriano R et al: LASIK outcomes in patients
with underlying systemic contraindications: a preliminary study. Ophthalmology 113:1118, 2006; Cornea Donor
Study Investigator Group: The effect of donor age on corneal transplantation outcome results of the cornea donor
study. Ophthalmology 115:620, 2008; Joseph A et al: Tacrolimus immunosuppression in high-risk corneal
grafts. Br J Ophthalmol 91:51, 2007; Kashani S, Mearza AA: Uses and safety profile of ciclosporin in ophthalmology.
Expert Opin Drug Saf 7:79, 2008; Kim JH et al: Novel technique of corneal biopsy by using a femtosecond laser
in infectious ulcers. Cornea 27:363, 2008; Mohammadpour M: Excimer laser refractive surgery in patients
with underlying autoimmune diseases. J Cataract Refract Surg 33:175, 2007; Pop M, Payette Y: Risk factors for
night vision complaints after LASIK for myopia. Ophthalmology 111:3, 2004; Reinhard T et al: Improvement of
graft prognosis in penetrating normal-risk keratoplasty by HLA class I and II matching. Eye 18:269, 2004; Sirikul T
et al: Predisposing factors and etiologic diagnosis of ulcerative keratitis. Cornea 27:283, 2008; Smith RJ, Maloney
RK: Laser in situ keratomileusis in patients with autoimmune diseases. J Cataract Refract Surg 32:1292, 2006.
|
