Peer Reviewed Publications

Out of 130 Peer-reviewed Publications

Post-LASIK Epithelial Dendritic Defect Associated With Alternaria.
Kocaturk T, Pineda R2nd, Green LK, Azar DT

PURPOSE: To report a case of a dendritic epithelial defect with interface inflammation associated with Alternaria sp. after laser in situ keratomileusis (LASIK) surgery.

METHODS: A case report of a 46-year-old woman who presented with a dendritic epithelial defect and interface inflammation after LASIK surgery.

RESULTS: After an apparent post-LASIK herpes simplex keratitis with related interface inflammation failed to respond to medical therapy, cornea culture results were positive for Alternaria fungal sp. 2 weeks and 6 days after presentation. Viral cultures and polymerase chain reaction were negative for herpes simplex virus. Six months after penetrating keratoplasty (and 1 year after LASIK), the patient underwent a cataract extraction OD. Best-corrected visual acuity 18 months after the original LASIK procedure was 20/25 OD.

CONCLUSIONS: Alternaria keratitis may present with a dendritic epithelial defect with interface inflammation mimicking herpes simplex virus.

Cornea.2007 Oct;26(9):1144-1146

Ectatic disorders associated with a claw-shaped pattern on corneal topography.
Lee BW, Jurkunas UV, Harissi-Dagher M, Poothullil AM, Tobaigy FM, Azar DT

PURPOSE: To identify clinical findings associated with claw-shaped patterns on corneal topography. DESIGN: Retrospective, observational case series.

METHODS: Forty eyes (26 patients) with classic claw-shaped patterns on corneal topography were identified from 3,993 Orbscan II records. They were subclassified into three groups: Group 1 (pellucid marginal degeneration [PMD] or PMD suspect); group 2 (keratoconus or keratoconus suspect); and group 3 (ectasia). The refractive and topographic indices of groups 1 and 2 were compared.

RESULTS: There were nine eyes (six patients) in group 1, 27 eyes (18 patients) in group 2, and four eyes (two patients) in group 3. The mean radii of maximal anterior (2.96 mm) and posterior (3.06 mm) elevation in group 1 were significantly greater than those of group 2 (1.89 mm; P = .018 and 1.72 mm; P = .022, respectively).

CONCLUSIONS: The claw-shaped pattern on corneal topography is not diagnostic of PMD; it is also seen in keratoconus.

Am J Ophthalmol. 2007 Jul;144(1):154-156

Comparison of EphA receptor tyrosine kinases and ephrinA ligand expression to EphB-ephrinB in vascularized corneas.
Kojima T, Chung TY, Chang JH, Sayegh R, Casanova FH, Azar DT

PURPOSE: Eph cell surface receptors and their ligands, ephrins, are involved in neuronal patterning and neovascularization. Our purpose is to compare and characterize the expression of ephrinA ligands and EphA receptors to ephrinB ligands and EphB receptors in excised mouse corneal tissue, in corneal epithelial and keratocyte cell lines, and during corneal angiogenesis.

METHODS: Mouse corneal epithelial cells and keratocytes were immortalized using SV40T antigen viral infection of primary cultures. The immortalized epithelial cells and keratocytes were cloned and characterized using antibodies to keratin, vimentin, integrin alpha5beta1, and alpha-smooth muscle actin. Basic fibroblast growth factor pellets were implanted to induce corneal neovascularization. The eyes of wild-type, ephrinB2(tlacZ/+), and EphB4(tlacZ/+) heterozygous mice were harvested and sectioned 7 days after pellet implantation. Confocal immunohistochemistry was performed to compare the expression of the Eph/ephrinA family (EphA1-8, ephrinA1-5) and Eph/ephrinB family (EphB1-4, EphB6 ephrinB1-3).

RESULTS: EphA1, EphA3, ephrinA1, ephrinA2, EphB1, EphB4, ephrinB1, and ephrinB2 were detected in wild-type mouse corneal epithelial cells and keratocytes. EphA2 was immunolocalized only in epithelial cells. Also, EphA3, ephrinA1, EphB1, EphB4, and ephrinB1 were immunolocalized to the corneal epithelium and stroma. In the vascularized corneas, ephrinB1 was immunolocalized mainly to the keratocytes around the vessels, and ephrinB2, EphB1, and EphB4 were colocalized mainly with CD31 to the vascular endothelial cells.

CONCLUSIONS: The characterization of ephrin ligand and Eph receptor expression during cornea angiogensis in this study suggests that the Eph/ephrin family of receptor tyrosine kinases and their ligands may play a role in the regulation of corneal angiogenesis.

Cornea. 2007 Jun;26(5):569-78

Corneal angiogenic privilege: angiogenic and antiangiogenic factors in corneal avascularity, vasculogenesis, and wound healing (an American Ophthalmological Society thesis).
Azar DT.

PURPOSE: To determine the molecular basis of corneal avascularity during wound healing and determine the role of angiogenic and antiangiogenic factors in corneal vasculogenesis.

METHODS: The expression of proangiogenic factors (vascular endothelial growth factor [VEGF]; basic fibroblast growth factor [bFGF]; matrix metalloproteinase-2 [MMP-2]; and membrane-type 1-MMP [MT1-MMP]) and antiangiogenic factors (pigment epithelium-derived factor [PEDF]; angiostatin; restin; and endostatin) was analyzed in avascular corneas and in models of corneal neovascularization (bFGF pellet implantation, intrastromal injection of MT1-MMP cDNA, and surgically induced partial limbal deficiency).

RESULTS: Immunohistochemistry demonstrated the presence of antiangiogenic factors (PEDF, angiostatin, restin, and endostatin) and proangiogenic molecules (VEGF, bFGF, MMP-2, and MT1-MMP) in the cornea after wounding. Proangiogenic MMPs were upregulated in stromal fibroblasts in the vicinity of invading vessels following bFGF pellet implantation. Corneal neovascularization (NV) was also induced by intrastromal injection of MT1-MMP naked cDNA in conjunction with de-epithelialization. Partial limbal deficiency (HLD-) resulted in corneal NV in MMP-7 and MMP-3 knockout mice but not in wild type controls.

CONCLUSIONS: Corneal angiogenic privilege is an active process involving the production of antiangiogenic factors to counterbalance the proangiogenic factors (which are upregulated after wound healing even in the absence of new vessels). Our finding that the potent antiangiogenic factors, angiostatin and endostatin, are colocalized with several MMPs during wound healing suggests that MMPs may be involved in the elaboration of these antiangiogenic molecules by proteolytic processing of substrates within the cornea.

Trans Am Ophthalmol Soc. 2006;104:264-302.

LASIK in the presbyopic age group: safety, efficacy, and predictability in 40- to 69-year-old patients.

Ghanem RC, de la Cruz J, Tobaigy FM, Ang LP, Azar DT.

OBJECTIVE: To report the safety, efficacy, and predictability of LASIK in a presbyopic population and to examine possible differences between age groups. DESIGN: Retrospective, descriptive, comparative consecutive case series.

PARTICIPANTS: Seven hundred ten eyes of 424 patients between 40 and 69 years of age who underwent LASIK by the same surgeon between January 1999 and September 2005. Patients had manifest refractive spherical errors ranging from -10.5 to +6 diopters (D) and cylinder of up to 2.50 D.

METHODS: LASIK was performed with IntraLase femtosecond laser or Hansatome microkeratomes and VISX Star (S4 or S2; VISX Inc., Santa Clara, CA) or Baush & Lomb Technolas 217z (Zyoptix or PlanoScan; Bausch & Lomb, Claremont, CA) excimer lasers. There were 511 myopic eyes (spherical equivalent [SE], -5.03+/-2.02 D) and 199 hyperopic eyes (SE, +2.21+/-1.21 D). Patients were divided into 3 groups: group 1 (40 to 49 years old; n = 359 eyes), group 2 (50 to 59 years old; n = 293 eyes), and group 3 (60 to 69 years old; n = 58 eyes).

MAIN OUTCOME MEASURES: Uncorrected visual acuity (UCVA) and best spectacle-corrected visual acuity (BSCVA), retreatment rates, safety, efficacy, and predictability.

RESULTS: The mean age of patients in groups 1, 2, and 3 was 45, 53, and 63 years, respectively. With increasing age, there was a trend toward higher retreatment rates and more myopic end points. Safety, efficacy, and predictability were comparable between all groups. At the final follow-up (mean+/-standard deviation, 10.4+/-7.4 months), 80% to 100% of eyes had 20/30 or better UCVA and 81% to 90% were within +/-1.00 D. No eyes lost more than 2 lines of BSCVA, and only 9 eyes (1.3%) lost 2 lines. Subgroup analysis of eyes with a follow-up of 12 months or more was performed. The results were compared with those with shorter follow-up. Both subgroups had comparable outcomes; the duration of follow-up did not affect the visual outcomes.

CONCLUSIONS: Despite a trend toward worse final BSCVA and higher retreatment rates in older patients, a greater risk of visual loss after LASIK was not observed. LASIK for myopia and hyperopia has reasonable safety, efficacy, and predictability profiles in the 40- to 69-year-old presbyopic population.

Ophthalmology. 2007 Jul;114(7):1303-10. Epub 2007 Mar 26.

Proangiogenic role of ephrinB1/EphB1 in basic fibroblast growth factor-induced corneal angiogenesis.
Kojima T, Chang JH, Azar DT.

Corneal neovascularization is a vision-threatening condition caused by various ocular pathological conditions. The aim of this study was to evaluate the function of the ephrin ligands and Eph receptors in vitro and in vivo in corneal angiogenesis in a mouse model. The Eph tyrosine kinase receptors and their ligands, ephrins, are expressed on the cell surface. The functions of Eph and ephrins have been shown to regulate axonal guidance, segmentation, cell migration, and angiogenesis. Understanding the roles of Eph and ephrin in corneal angiogenesis may provide a therapeutic intervention for the treatment of angiogenesis-related disorders. Immunohistochemical studies demonstrated that ephrinB1 and EphB1 were expressed in basic fibroblast growth factor (bFGF)-induced vascularized corneas. EphB1 was specifically colocalized with vascular endothelial marker CD31 surrounded by type IV collagen. EphrinB1 was expressed in corneal-resident keratocytes and neutrophils. Recombinant ephrinB1-Fc, which induces EphB receptor activation, enhanced bFGF-induced tube formation in an in vitro aortic ring assay and promoted bFGF-induced corneal angiogenesis in vivo in a corneal pocket assay. Synergistically enhanced and sustained activation of extracellular signal-regulated kinase was noted in vascular endothelial cell lines after stimulation with ephrin B1 and bFGF combinations. These results suggest that ephrinB1 plays a synergistic role in corneal neovascularization.

Am J Ophthalmol 2007 Feb;170(2):764-73.

A control-matched comparison of laser epithelial keratomileusis and laser in situ keratomileusis for low to moderate myopia.
Tobaigy FM, Ghanem RC, Sayegh RR, Hallak JA, Azar DT.

PURPOSE: To compare the visual and refractive outcomes of laser epithelial keratomileusis (LASEK) and laser in situ keratomileusis (LASIK) for the treatment of low to moderate myopia.

DESIGN: Retrospective, nonrandomized, control-matched study.

METHODS: The charts of 2257 eyes that underwent LASEK or LASIK treatment were reviewed. Patients who were 21 years of age or older having between -0.75 and -6.00 diopters (D) of myopia with up to -2.25 D of astigmatism were included. One hundred twenty-two LASEK-treated eyes were matched with 122 LASIK-treated eyes having preoperative spheres, cylinders, and spherical equivalent (SE) within +/-0.50 D. Both groups had similar preoperative best spectacle-corrected visual acuity (BSCVA), laser platform, and follow-up durations. Outcome measures were visual and refractive results.

RESULTS: Preoperatively, the mean SE was -3.50 +/- 1.40 D for LASEK and -3.50 +/- 1.42 D for LASIK (P = .59). Postoperatively, the mean logarithm of minimum angle of resolution (logMAR) uncorrected visual acuity (UCVA) was 0.01 +/- 0.08 (20/21) for LASEK and 0.06 +/- 0.12 (20/23) for LASIK; the mean SE was -0.15 +/- 0.40 D for LASEK and -0.37 +/- 0.45 D for LASIK; and the mean logMAR of BSCVA was -0.03 +/- 0.06 (20/19) for LASEK and -0.02 +/- 0.05 (20/19) for LASIK. No eye lost 2 or more lines of BSCVA in both groups.

CONCLUSIONS: Slight differences in the visual and refractive results between LASEK and LASIK were observed, despite the use of the same nomogram. Both procedures were safe, effective, and predictable. Nomogram adjustment may be necessary for LASIK surgeons adopting surface ablation.

Am J Ophthalmol 2006 Dec;142(6):901-8. Epub 2006 Sep 8

Ablation on the undersurface of a LASIK flap. Instrument and method for continuous eye tracking]

Taneri S, Azar DT.

BACKGROUND: The risk of iatrogenic keratectasia after laser in situ keratomileusis (LASIK) increases with thinner posterior stromal beds. Ablations on the undersurface of a LASIK flap could only be performed without the guidance of an eye tracker, which may lead to decentration. A new method for laser ablation with flying spot lasers on the undersurface of a LASIK flap was developed that enables the use of an active eye tracker by utilizing a novel instrument. The first clinical results are reported.

PATIENTS AND METHODS: Patients wishing an enhancement procedure were eligible for a modified repeat LASIK procedure if the flaps cut in the initial procedure were thick enough to perform the intended additional ablation on the undersurface leaving at least 90 microm of flap thickness behind. (1) The horizontal axis and the center of the entrance pupil were marked on the epithelial side of the flap using gentian violet dye. (2) The flap was reflected on a newly designed flap holder which had a donut-shaped black marking. (3) The eye tracker was centered on the mark visible in transparency on the flap. (4) Ablation with a flying spot Bausch & Lomb Technolas 217z laser was performed on the undersurface of the flap with a superior hinge taking into account that in astigmatic ablations the cylinder axis had to be mirrored according to the formula: axis on the undersurface=180 degrees -axis on the stromal bed. (5) The flap was repositioned.

RESULTS: Detection of the marking on the modified flap holder and continuous tracking instead of the real pupil was possible in all of the 12 eyes treated with this technique. It may be necessary to cover the real pupil during ablation in order not to confuse the eye tracker. Ablation could be performed without decentration or loss of best spectacle-corrected visual acuity. Refractive results in minor corrections were good without nomogram adjustment.

CONCLUSIONS: Using this novel flap holder with a marking that is tracked instead of the real pupil, centered ablations with a flying spot laser on the undersurface of a LASIK flap are feasible. Thus, the additional risk of iatrogenic keratectasia associated with stromal enhancement ablations is avoided.

Opthalmologe 2007 Feb;104(2):132-6.

Identical excimer laser PTK treatments in rabbits result in two distinct haze responses.

McCally RL, Connolly PJ, Stark WJ, Jain S, Azar DT

PURPOSE: To obtain objective light-scattering measurements to test a hypothesis that identical PTK treatments cause distinct low- and high-level light-scattering responses in rabbit corneas.

METHODS: An excimer laser was used to produce identical 6-mm diameter phototherapeutic keratectomy treatments (PTK) in 32 pigmented rabbits. Eyes were treated by performing a 40-microm epithelial ablation, followed by a 100-mum stromal PTK. Objective scattering measurements were made before treatment, weekly up to 5 weeks, and then biweekly to 9 weeks. Confocal microscopy was performed on several corneas at 4 and 7 weeks.

RESULTS: Mean scattering levels split into distinct low- and high-scattering groups 2 weeks after treatment and remained distinct until week 7 (P < 0.003). Scattering in the low group reached a broad peak that lasted from weeks 2 to 4 at approximately 3 times the pretreatment level. Scattering in the high group peaked at 3 weeks at approximately 12 times the pretreatment level. Scattering levels diminished after reaching their peaks. Confocal images showed a band of highly reflective material in the anterior stroma that extended much deeper in corneas from the high group. The reflective band in the highly scattering corneas obscured the posterior stroma from view for up to 5 weeks.

CONCLUSIONS: Quantitative scattering data obtained with the scatterometer suggest that identical PTK treatments indeed result in distinct low- and high-level light-scattering responses in rabbits.
Invest Ophthalmol Vis Sci 2006 Oct;47(10):4288-94

Potential complications of ocular surgery in patients with coexistent keratoconus and Fuchs' endothelial dystrophy.

Jurkunas U, Azar DT

PURPOSE: To describe the potential complications of cataract and refractive surgery in patients with Fuchs' endothelial dystrophy (FED) and keratoconus.

DESIGN: Retrospective case series.

PARTICIPANTS: Eight patients with FED and keratoconus in a large university group practice.

METHODS: We reviewed the clinical and topographic findings of 8 patients (15 eyes) with FED and keratoconus. Clinical examination, corneal topography, specular microscopy were done, and sequential central corneal thickness (CCT) was obtained. Follow-up ranged from 1 month to 6 years.

MAIN OUTCOME MEASURES: Findings of keratoconus and FED in preoperative evaluation. RESULTS: Five patients had concomitant cataracts; 3 had refractive errors and sought surgical correction. Cataract surgery was performed on 3 of 5 patients (5 eyes). LASIK was performed on one eye of 3 patients. Of 5 eyes that underwent cataract extraction, 4 had blurry vision after surgery. The interval between the surgical procedure and onset of symptoms ranged from 1 month to 4 years. The causes of decreased vision after cataract surgery were corneal edema and/or corneal ectasia. The CCT readings ranged from 426 to 824 microm. One of 4 symptomatic eyes underwent penetrating keratoplasty. The CCTs of 3 patients (6 eyes) who presented with refractive error ranged from 507 to 565 microm. One eye had undergone an attempted LASIK procedure resulting in a lost cap. Corneal topography and specular microscopy showed the coexistence of keratoconus and FED, and the patients were advised against having LASIK surgery.

CONCLUSIONS: Corneal thinning caused by keratoconus and concurrent increase in corneal thickness caused by FED may combine to normalize the corneal pachymetry readings; disease severity may be underestimated, which may lead to unexpected postoperative visual outcomes. Routine use of preoperative topography and specular microscopy may help to avert potential surgical complications.

Ophthalmology 2006 Dec;113(12):2187-97. Epub 2006 Sep 25

Femtosecond-laser arcuate wedge-shaped resection to correct high residual astigmatism after penetrating keratoplasty.

Ghanem RC, Azar DT.

We describe a standardized technique of femtosecond (FS) laser arcuate resection (LAR) in which intersecting arcuate cuts are used to perform a wedge resection for the correction of high astigmatism. A simple formula was used to calculate the relative decentration of the arcuate cuts based on the radii of curvature and desired wedge width to be resected. Feasibility of the procedure was established in porcine corneas before treatment of a patient with 20 diopters (D) of post-keratoplasty astigmatism. The astigmatism was reversed. Suture removal resulted in reduction of 14.5 D of astigmatism. Laser arcuate resection can be an effective alternative to manual wedge resection, allowing easier, more controlled, and more precise excision of tissue in width, length, and depth
.J Cataract Refract Surg 2006 Sep;32(9):1415-9.

Anti-angiogenic therapy: Prospects for treatment of ocular tumors.
Rosenblatt MI, Azar DT

The growth of new blood vessels (angiogenesis) within tumors is essential for tumor growth, maintenance, and metastasis. Angiogenesis research has identified a host of pro- and anti-angiogenic factors that regulate an "angiogenic switch," which when turned on, allows tumors to assume a more aggressive form. Angiogensis inhibitors that target this switch are in clinical trials for a wide array of tumor types. Although angiogenesis inhibitors are already widely used to treat ocular disease, only limited case reports are currently available for the use of angiogenesis inhibitors to treat ocular tumors. Evidence for angiogenesis in the growth and spread of uveal melanoma, retinoblastoma, and von Hippel Lindau (VHL) disease exists. The very limited trials of angiogenesis inhibitors in the treatment of uveal melanoma and VHL are promising, although more extensive controlled trials will be needed to confirm their efficacy.

Semin Ophthalmol 2006 Jul-Sep;21(3):151-60.

Basement membrane and collagen deposition after laser subepithelial keratomileusis and photorefractive keratectomy in the leghorn chick eye.
Javier JA, Lee JB, Oliviera HB, Chang JH, Azar DT.

OBJECTIVE: To evaluate corneal scar formation and new collagen deposition after laser subepithelial keratomileusis (LASEK) compared with photorefractive keratectomy (PRK) in the leghorn chick corneal model.

METHODS: Leghorn chick corneas treated with LASEK surgery (using 20% ethanol for 30 seconds) or PRK were evaluated by indirect confocal immunofluorescence and transmission electron microscopy at 1, 2, 7, 14, and 28 days after surgery. New collagen deposition was determined by dichlorotriazinylaminofluorescein staining 2 and 4 weeks after surgery.

RESULTS: Laminin was detected around the basal layers during the immediate postoperative period and 4 weeks after LASEK surgery, and from day 2 onwards after PRK. Collagen III deposition in the cornea was about 3 times greater with PRK than with LASEK. The thickness of new collagen deposition at 4 weeks was 34 microm +/- 2.5 microm in the PRK group, which was significantly greater than that of the LASEK group (11 microm +/- 1 microm; P<.001).

CONCLUSIONS: Reduced subepithelial stromal tissue deposition was observed in LASEK-treated eyes compared with PRK-treated eyes. Postoperative preservation of the epithelial basement membrane and survival of epithelial cells in LASEK and possibly in epithelial laser in situ keratomileusis may contribute to this phenomenon.

CLINICAL RELEVANCE: An advantage of LASEK over PRK is the reduction of postoperative haze.
Arch Ophthalmol 2006 May;124(5):703-9

Laser eye surgery for refractive errors.
Sakimoto T, Rosenblatt MI, Azar DT.

Several laser and non-laser refractive surgical procedures have been used to modify the shape of the cornea and correct myopia, hyperopia, astigmatism, and presbyopia. Introduction of the excimer laser to reshape the cornea has resulted in remarkable developments in the correction of these refractive errors. Combined with other advanced ophthalmological instruments, laser refractive eye surgery has resulted in a substantial rise in the safety, efficacy, and predictability of surgical outcomes. Despite these advances, certain limitations and complications persist. In this review, we describe the history, preoperative assessment, surgical techniques, outcomes, and complications of laser refractive surgery.

Lancet. 2006 Apr 29;367(9520):1432-47.

Optimal size and location for corneal rotational autografts: a simplified mathematical model.
Afshari NA, Duncan SM, Tanhehco TY, Azar DT.

OBJECTIVE: To calculate clinical guidelines for the optimal location and size of a rotational autokeratoplasty.

METHODS: The ideal graft size and trephine decentration for a rotational autograft were calculated based on scar location using geometric models. Mathematical variables were set to maximize postoperative visual acuity and for generalization of the geometric model. This model was used in a rotational autokeratoplasty of a patient with a history of a corneal scar and diplopia. An 8-mm autograft was decentered 0.5 mm superiorly and rotated 180 degrees to relocate the scar to the superior aspect of the cornea, out of the patient's vision.

RESULTS: For cases that satisfy the given variables, a graft diameter of 8 mm with a decentration of 0.5 mm balances maximization of scar removal and scar movement superiorly, with minimization of discrepancy in corneal thickness after rotation. For scars that are alpha degrees from horizontal, the graft should be rotated 180 - alpha degrees . By using these calculations, the autograft in this case successfully resolved the diplopia and improved visual acuity.

CONCLUSIONS: A rotational autograft can be an effective alternative to standard penetrating keratoplasty for some patients with corneal scars. We establish a mathematical model for most clinical instances of a rotational autograft, in which an 8-mm graft with a decentration of 0.5 mm best satisfies the goals of surgery.

Arch Ophthalmol 2006 Mar;124(3):410-3.

Mitomycin-C assisted photorefractive keratectomy in the treatment of buttonholed laser in situ keratomileusis flaps associated with epithelial ingrowth.

Teneri S, Koch JM, Melki SA, Azar DT

The prophylactic intraoperative use of mitomycin-C (MMC) to prevent haze and scarring after excimer laser surface ablation (phototherapeutic/photorefractive keratectomy [PTK/PRK]) in an eye with a previous laser in situ keratomileusis (LASIK) flap buttonhole with epithelial ingrowth is described. A well-centered buttonhole measuring 2.0 mm in diameter was cut within a thin LASIK flap in an amblyopic eye. Over the next 8 weeks, corneal haze and progressive epithelial ingrowth formed centrally. An early transepithelial PTK/PRK approach was chosen to manage the buttonhole together with the epithelial ingrowth and to treat ametropia before the onset of scarring. The approach included epithelial removal with PTK, application of MMC 0.02% for 1 minute, irrigation, a short waiting period to allow for diffusion, PRK correction of -4.0 diopters without nomogram adjustment, and bandage contact lens. A regimen of prednisolone acetate 1% and ofloxacin 0.03% 5 times a day for 1 week (steroid tapered) was prescribed. Epithelial ingrowth was removed successfully. Minimal haze formation was visible 2 weeks after the retreatment but did not reduce best spectacle-corrected visual acuity (BSCVA) and resolved within the next few weeks. After 6 weeks, uncorrected visual acuity was equal to BSCVA preoperatively (20/50). There was no evidence of recurrent epithelial ingrowth or central scarring after 24 months. Transepithelial PTK/PRK was effective in managing central epithelial ingrowth in a buttonholed LASIK flap. Prophylactic intraoperative use of MMC may reduce haze formation and corneal scarring in early treatments and may also prevent recurrent epithelial ingrowth. This approach may offer faster visual recovery and no risk for a repeated buttonhole creation compared with the widespread recutting a new flap after a couple of months. The optimal application time and concentration of MMC need to be established.

J Cataract Refract Surg. 2005 Oct;31(10):2026-30.

Proteomic identification of activin receptor-like kinase-1 as a differentially expressed protein during hyaloid vascular system regression.
Albe E, Escalona E, Rajagopal R, Javier JA, Chang JH, Azar DT.

The hyaloid vascular system (HVS) is a transient network of capillaries that nourishes the embryonic lens and the primary vitreous of the developing eye. We used proteomic analysis and immunohistochemical staining to identify activin receptor-like kinase-1 (ALK1), a type I receptor for transforming growth factor-beta1, during the HVS regression phase. In addition, we overexpressed ALK1 in corneas implanted with bFGF (basic fibroblast growth factor) pellets and observed that ALK1 overexpression resulted in inhibition of bFGF-induced corneal neovascularization in vivo. Our data suggest that ALK1 may play a role in HVS regression during ocular development.

FEBS Lett 2005 Oct 24;579(25):5481-6. Epub 2005 Sep 28.

Successful treatment of Fusarium endophthalmitis with voriconazole and Aspergillus endophthalmitis with voriconazole plus caspofungin.
Durand ML, Kim IK, D'Amico DJ, Loewenstein JI, Tobin EH, Kieval SJ, Martin SS, Azar DT, Miller FS 3rd, Lujan BJ, Miller JW.

PURPOSE: To report successful treatment of exogenous Fusarium and Aspergillus endophthalmitis with new antifungal agents.

DESIGN: Interventional case report.

METHODS: Treatment of two cases is reviewed. RESULTS: A 64-year-old man developed post-cataract Fusarium moniliforme endophthalmitis. Infection persisted despite removal of the intraocular lens, three vitrectomies, and five intravitreal injections of amphotericin. Inflammation resolved and vision improved from 20/80 to 20/40 on 6 months of oral voriconazole. A 55-year-old man developed post-cataract intraocular inflammation. After three vitrectomies and removal of the intraocular lens, Aspergillus fumigatus endophthalmitis was diagnosed. Intravitreal amphotericin and systemic voriconazole were given, but one week later there were early signs of recurrence. Intravenous caspofungin was added and the eye improved. Caspofungin was continued for 6 weeks and voriconazole for 6 months. Vision improved from counting fingers to 20/80 at 6 months and 20/25 at 23 months.

CONCLUSION: Voriconazole is a promising new therapy for Fusarium and Aspergillus endophthalmitis. Caspofungin may act synergistically with voriconazole in treating Aspergillus endophthalmitis.

Am J Ophthalmol 2005 Sep;140(3):552-4.

Functional characterization of neostatins, the MMP-derived, enzymatic cleavage products of type XVIII collagen.
Chang JH, Javier JA, Chang GY, Oliviera HB, Azar DT.

Several anti-angiogenic factors are derived from proteolytic processing of large molecules including endostatin from type XVIII collagen and angiostatin from plasminogen. In previous studies we showed that neostatin-7, the C-terminal 28kDa endostatin-spanning proteolytic fragment, is generated from the proteolytic action of matrix metalloproteinase matrilysin (MMP)-7 on type XVIII collagen. Now, we report a second member of the neostatin family of proteins, neostatin-14. Given the small quantities of neostatin-7 and -14 generated by the breakdown of naturally occurring collagen XVIII (using MMP-7 and -14, respectively), we used two other approaches to characterize the anti-angiogenic properties of these molecules: murine recombinant neostatin in vitro, and gene therapy. We demonstrate that murine recombinant neostatin-7 inhibits calf pulmonary artery endothelial cell proliferation and that microinjection of neostatin-7 and neostatin-14 naked DNA into the corneal stroma of mice results in significant reduction of basic fibroblast growth factor-induced corneal neovascularization. These results provide supportive evidence of the possible anti-angiogenic effect of neostatins.

FEBS Lett. 2005 Jul 4;579(17):3601-6.

[LASEK: results after 1 year. Retrospective analysis based on the dioptric power matrix for moderate myopic and astigmatic correction]
Taneri S, Azar DT.

PURPOSE: The aim of this study was to assess astigmatism magnitude and axis changes based on the dioptric power matrix in low to moderate levels of myopia and astigmatism treated with LASEK.

PATIENTS AND METHODS: This retrospective analysis included 54 myopic eyes treated with LASEK with a minimum follow-up of 12 months. An epithelial flap was created by 25-45 s of 20% alcohol exposure. The corneal surface was ablated using two different excimer lasers and nomogram adjustment. The flap was repositioned and a bandage applied to the contact lens. Main outcome measures were manifest refraction as calculated with the dioptric power matrix, UCVA, BSVCA, and retreatment rate.

RESULTS: Mean manifest refraction is shown in table 2 (Tabelle 2). UCVAs of 20/20 or better were found in 33% of eyes at 1 week and in more than 53% at 3 months to 1 year. The safety index remained > or =0.98 after postoperative week 4. The efficacy index varied between 0.91 and 0.98 after 1 month.

CONCLUSION: LASEK for correction of low to moderate myopia and astigmatism seems to be a safe, effective, and stable option.

Ophthalmologe 2005 Mar;102(3):235-40.

Evolution, techniques, clinical outcomes, and pathophysiology of LASEK: review of the literature.
Taneri S, Zieske JD, Azar DT.

Laser subepithelial keratomileusis (LASEK) is a relatively new laser surgical procedure that combines certain elements of both laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) to improve the risk/benefit ratio. Diluted alcohol is used to loosen the epithelial adhesion to the corneal stroma. The loosened epithelium is moved aside from the treatment zone as a hinged sheet. Laser ablation of the subepithelial stroma is performed before the epithelial sheet is returned to its original position. We reviewed the literature regarding modifications of the technique, indications, outcomes, and complications, as well as wound healing after LASEK surgery. This literature review of 1,421 LASEK-treated eyes provided many findings: 1) The long-term stable results in the absence of serious complications, such as infections, recurrent erosions, scars, or late-onset corneal haze formation in patients re-examined up to 5 years after LASEK; 2) Epithelial closure with recovery of functional vision was completed at days 4 to 7 in most cases; 3) A tendency toward overcorrection with PRK nomograms; 4) We hypothesize that this tendency may be due to the decreased wound healing response, which may lead to myopic regression in PRK; and 5) Postoperative discomfort and prolonged visual recovery until the epithelium closes remain the biggest disadvantages of LASEK compared to LASIK. LASEK surgery is especially valuable in patients with thin corneas who would not qualify for LASIK surgery. However, a potential superiority of LASEK to LASIK in wavefront guided ablations still remains speculative.

Surv. Ophthalmol 2004 Nov-Dec;49(6):576-602

Photochemical keratodesmos as an adjunct to sutures for bonding penetrating keratoplasty corneal incisions.Proano CE, Azar DT, Mocan MC, Redmond RW, Kochevar IE.

PURPOSE: To evaluate the benefit of photochemical keratodesmos (PKD) in acute wound closure of penetrating keratoplasty (PKP) corneal incisions in vivo.

SETTING: Massachusetts General Hospital and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.

METHODS: Penetrating keratoplasty incisions were performed in both eyes of 6 New Zealand white rabbits, followed by application of 1.5 mM rose bengal dye at the wound edges. The incision in 1 eye of each rabbit was irradiated with neodymium:YAG laser light at 532 nm and fluence of 40 J/cm2; the contralateral control eye was untreated. Intraocular pressure at which fluid leaked at the edges (IOPL) was determined immediately after surgery.

RESULTS: The mean IOPL was 410 mm Hg +/- 70 (SD) in the PKD-treated eyes and 250 +/- 150 mm Hg in the unirradiated eyes. The difference was statistically significant by paired t test (P<.05).

CONCLUSIONS: Photochemical keratodesmos may be a useful adjunct to sutures for approximating PKP corneal incisions in the immediate postoperative period. This process does not induce high temperature, and thus denaturation can be avoided and structural integrity restored.

J Cataract Refract Surg 2004 Nov;30(11):2420-4.

Combined ICRS insertion and LASIK to maximize postoperative residual bed thickness in high myopia.
Mian SI, Jarade EF, Scally A, Azar DT.

PURPOSE: To describe a new technique and early outcomes of combined intrastromal corneal ring segment (ICRS) insertion and laser in situ keratomileusis (LASIK) to treat patients with moderate to high myopia and thin corneas.

SETTING: University-based academic practice, Boston, Massachusetts, USA.

METHODS: Combined ICRS insertion and LASIK was performed in 2 stages: ICRS channel formation (stage I) followed by LASIK and ICRS insertion (stage II).

RESULTS: Fifteen eyes of 11 patients with a mean preoperative spherical equivalent of -9.98 diopters (D) +/- 2.60 (SD) (range -7.13 to -16.25 D) and mean preoperative astigmatism of 1.11 +/- 0.75 D (range 0.00 to -3.00 D) were treated with combined ICRS insertion and LASIK. The mean central pachymetry was 526.13 +/- 35.69 microm (472 to 579 microm). The uncorrected visual acuity was 20/40 or better in 7 of 15 eyes (46.67%) at 1 month, 6 of 12 eyes (50.00%) at 3 months, 5 of 12 eyes (41.67%) at 6 months, and 6 of 12 eyes (50.00%) at 12 months. The best spectacle-corrected visual acuity was 20/40 or better at all times. Postoperative maps confirmed the absence of ectasia. The postoperative spherical equivalent was within +/-1.00 D of the intended refraction in 11 of 15 eyes (73.33%) at 1 month, 9 of 12 eyes at 3 and 6 months, and 8 of 12 eyes (66.67%) at 12 months.

CONCLUSIONS: Results of combined ICRS insertion and LASIK in moderately to highly myopic patients with relatively thin corneas were good. Long-term studies are needed to determine whether this procedure will decrease the risk of LASIK-induced keratectasia in these patients

.J Cataract Refract Surg 2004 Nov;30(11):2383-90.

Safety, efficacy, and stability indices of LASEK correction in moderate myopia and astigmatism.
Taneri S, Feit R, Azar DT

PURPOSE: To evaluate the visual outcomes and complications in low to moderate levels of myopia and astigmatism treated with laser-assisted subepithelial keratectomy (LASEK) with a focus on postoperative recovery.

SETTING: Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA.

METHODS: A retrospective analysis of a case series of eyes treated with LASEK from 1996 to July 2002 with a follow-up of 2 years was performed. The LASEK technique involved creating an epithelial flap with 25 to 45 seconds of exposure to 20% alcohol, ablating the corneal surface using 3 different excimer lasers and nomogram adjustment, and repositioning the flap and applying a bandage contact lens. The main outcome measures were uncorrected visual acuity (UCVA), efficacy index, manifest refraction, best spectacle-corrected visual acuity (BSCVA), safety index, retreatment rate, and complications.

RESULTS: One hundred seventy-one eyes (85 right eyes and 86 left eyes) of 105 patients were studied. Preoperatively, the mean spherical equivalent was -2.99 diopters (D) +/- 1.43 (SD) (range -0.38 to -7.75 D) and the mean cylinder, -0.78 +/- 0.73 D. The UCVA ranged from 20/800 to 20/32, and the BSCVA ranged from 20/63 to 20/16; the median was 20/20. One week postoperatively, 96% of eyes had a UCVA of 20/40 or better but definitive visual recovery took more than 4 weeks in some eyes. Approximately 95% of eyes were within +/-1.0 D of emmetropia after 4 to 52 weeks; the remaining 5% did not show major deviations. At 4 to 52 weeks, only 1 eye was overcorrected by more than 1.0 D of manifest refraction. The safety index remained close to 1.0 for the follow-up after 4 weeks. The efficacy index displayed a plateau at 0.9 from 1 month to 1 year. No serious complication (including recurrent erosion syndrome) was encountered. The mean follow-up was 31 weeks, and the retreatment rate was 2.9% up to 2 years of follow-up.

CONCLUSIONS: The long-term safety and effectiveness of LASEK for the correction of low to moderate myopia and astigmatism were demonstrated. The treatment effect stabilized after 4 weeks.

J Cataract Refract Surg 2004 Oct;30(10):2130-7.

Photochemical keratodesmos for bonding corneal incisions.
Proano CE, Mulroy L, Jones E, Azar DT, Redmond RW, Kochevar IE.

PURPOSE: To evaluate the immediate and long-term effectiveness of a dye-plus-laser irradiation treatment (photochemical keratodesmos [PKD]) for sealing corneal incisions.

METHODS: Incisions (3.5 mm) in rabbit corneas were treated on the incision walls with rose bengal dye followed by exposure to 514-nm laser radiation. PKD was evaluated in three groups (n = 3-6) using laser fluences of 115, 153, or 192 J/cm(2) (180-, 240-, and 300- second exposures, respectively) compared with an untreated group (n = 8). The intraocular pressure at which leakage occurred (IOP(L)) during infusion of saline into the anterior chamber was determined. In a long-term study, treated and control corneas were observed weekly for 10 weeks for the appearance of neovascularization, anterior chamber inflammation, iridocorneal adhesion, corneal melting, and scarring. RESULTS: Immediately after treatment, the IOP(L) increased with increasing laser fluence, producing IOPs of 230 +/- 90, 370 +/- 120, and more than 500 mm Hg at 115, 153, and 192 J/cm(2), respectively, compared with 40 +/- 20 mm Hg in control eyes (P < 0.005). No reduction in the IOP(L) was observed up to 14 days after surgery. Corneal melting in PKD-treated or control eyes was not observed in the 10-week healing study. Neovascularization, which peaked at 4 weeks but resolved by 8 weeks, was detected around the incision in both PKD-treated and control eyes.

CONCLUSIONS: Immediate and lasting sealing of corneal incisions was obtained in eyes treated with PKD, using short irradiation times. These results suggest that PKD has potential for improved corneal tissue bonding.

Invest Ophthalmol Vis Sci 2004 Jul;45(7):2177-81

The future of wavefront sensing and customization.
Yeh SI, Azar DT.

The possibility of achieving supernormal vision in terms of acuity and contrast has fueled the imagination and creativity of vision researchers to pursue the goal of customized wavefront refractive surgery. This goal is achieved by generating an optimal ablation pattern based on individual anatomical and functional characteristics of the treated eye. However, increasing concerns regarding the clinical applicability of customized wavefront correction have emerged, and the possibility of achieving supernormal vision in all patients has been challenged. It is by understanding current optical, physiologic,and technological challenges faced by treating physicians and basic researchers that we can develop clear objectives for the future development of customized refractive surgery.

Ophthalmol Clin North Am. 2004 Jun;17(2):247-60, viii.

Corneal asphericity change after excimer laser hyperopic surgery: theoretical effects on corneal profiles and corresponding Zernike expansions.
Gatinel D, Malet J, Hoang-Xuan T, Azar DT.

PURPOSE: To determine the theoretical relationships between the changes in corneal paraxial power, asphericity, and the corresponding Zernike polynomial expansion after conventional and customized excimer laser correction of hyperopia.

METHODS: The initial corneal profile was modeled as a conic section of apical radius of curvature R1 and asphericity Q1. The theoretical value of the postoperative apical radius of curvature R2 was computed by using a paraxial formula from the value of R1 and hyperopic defocus D. The postoperative asphericity Q2 of the corneal surface was computed within the optical zone of diameter S after the delivery of a Munnerlyn-based profile of ablation for hyperopia using conic section-fitting and minimization of the squared residuals. These calculations were repeated for different values of defocus, initial apical radius of curvature, and asphericity. Taylor series expansions were also used to provide an approximation aimed at predicting change in asphericity. The coefficients of a Zernike polynomial expansion of the rotationally symmetrical corneal profile (defocus C2(0), spherical aberration C4(0), secondary spherical aberration C6(0)) were also computed, by using scalar products applied to the considered corneal profile modeled as a conic section and were expressed as a function of both its apical radius and asphericity. This allowed approximation of the variations of the Zernike polynomial expansion of the corneal profiles by subtracting the postoperative coefficient weighting a particular aberration from that of the preoperative one in different theoretical situations, after both conventional and customized hyperopia treatments aimed at controlling the postoperative corneal asphericity and delivered over a normalized pupil diameter.

RESULTS: Conical least-squares fitting was unambiguous, allowing approximation of the postoperative corneal profile as a conic section of apical radius R2. After a Munnerlyn-based hyperopia treatment, the sign of the asphericity of this profile remains theoretically unchanged, but its value decreased for initially oblate and increased for initially prolate corneas, respectively. A similar trend was noted with the approximation obtained by the Taylor series expansion. The alteration of the apical radius and/or of the asphericity of the corneal surface resulted in variations of both the corneal profile Zernike coefficients C2(0) and C4(0). The former was essentially dependent on the variation of the apical radius and the latter essentially on the variation of both apical radius and asphericity.

CONCLUSIONS: Conventional and customized profiles of ablation for hyperopia alter the postoperative corneal asphericity and the Zernike coefficients of the corneal profile. The results of this study may be useful in the interpretation of the postoperative variations of the corneal profile and their impact on corneal wavefront expansion variations after both conventional and customized profiles of ablation.

Invest. Ophthalmol Vis Sci 2004 May;45(5):1349-59