Subclinical Keratoconus Detection and Characterization Using Motion-Tracking Brillouin Microscopy.

PURPOSE: To characterize focal biomechanical alterations in subclinical keratoconus (SKC) using motion-tracking (MT) Brillouin microscopy and evaluate the ability of MT Brillouin metrics to differentiate eyes with SKC from normal control eyes. DESIGN: Prospective cross-sectional study. PARTICIPANTS: Thirty eyes from 30 patients were evaluated, including 15 eyes from 15 bilaterally normal patients and 15 eyes with SKC from 15 patients. METHODS: All patients underwent Scheimpflug tomography and MT Brillouin microscopy using a custom-built device. Mean and minimum MT Brillouin values within the anterior plateau region and anterior 150 µm were generated. Scheimpflug metrics evaluated included inferior-superior (IS) value, maximum keratometry (Kmax), thinnest corneal thickness, asymmetry indices, Belin/Ambrosio display total deviation, and Ambrosio relational thickness. Receiver operating characteristic (ROC) curves were generated for all Scheimpflug and MT Brillouin metrics evaluated to determine the area under the ROC curve (AUC), sensitivity, and specificity for each variable. MAIN OUTCOME MEASURES: Discriminative performance based on AUC, sensitivity, and specificity. RESULTS: No significant differences were found between groups for age, sex, manifest refraction spherical equivalent, corrected distance visual acuity, Kmax, or KISA% index. Among Scheimpflug metrics, significant differences were found between groups for thinnest corneal thickness (556 µm vs. 522 µm; P < 0.001), IS value (0.29 diopter [D] vs. 1.05 D; P < 0.001), index of vertical asymmetry (IVA; 0.10 vs. 0.19; P < 0.001), and keratoconus index (1.01 vs. 1.05; P < 0.001), and no significant differences were found for any other Scheimpflug metric. Among MT Brillouin metrics, clear differences were found between control eyes and eyes with SKC for mean plateau (5.71 GHz vs. 5.68 GHz; P < 0.0001), minimum plateau (5.69 GHz vs. 5.65 GHz; P < 0.0001), mean anterior 150 µm (5.72 GHz vs. 5.68 GHz; P < 0.0001), and minimum anterior 150 µm (5.70 GHz vs. 5.66 GHz; P < 0.001). All MT Brillouin plateau and anterior 150 µm mean and minimum metrics fully differentiated groups (AUC, 1.0 for each), whereas the best performing Scheimpflug metrics were keratoconus index (AUC, 0.91), IS value (AUC, 0.89), and IVA (AUC, 0.88). CONCLUSIONS: Motion-tracking Brillouin microscopy metrics effectively characterize focal corneal biomechanical alterations in eyes with SKC and clearly differentiated these eyes from control eyes, including eyes that were not differentiated accurately using Scheimpflug metrics. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The biology of corneal cross-linking derived from ultraviolet light and riboflavin.

Over the past 20 years, corneal crosslinking (CXL) has been used by surgeons to halt progression in eyes with keratoconus. We reviewed the literature regarding the mechanism of action of CXL, the role of each of its components the strong biologic reaction, and their effects on cell interaction, proteins involved, wound healing, and cytotoxic reaction. CXL surgery involves a photochemical response in which ultraviolet light at a given wavelength and riboflavin participate. The combination of irradiation with UVA light and riboflavin leads to an intense process of apoptosis of keratocytes in the anterior stroma. Differences in light irradiation, as well as the importance of riboflavin and its vehicle, were also detailed. The surgery creates additional chemical bonds between the amino terminals of the collagen side chains and the proteoglycans of the extracellular matrix. A photosensitization reaction catalyzed by riboflavin classically involves the production of singlet oxygen. Microstructure studies show changes in the size of the fibril and potentially in the interfibrillar space, that the most significant changes related to the stiffening effect of CXL occur in the anterior third of the cornea and that short irradiation times, especially below 5 min, may not have the same biological effect. Changes in the riboflavin vehicle, with the incorporation of Hydroxypropyl methylcellulose as a carrier, can lead to faster diffusion and a more intense photochemical reaction. These are findings that can impact the optimal adjustment of irradiation time according to the riboflavin (and its carrier) used. Many studies have suggested that CXL is safe and effective in the standard and accelerated protocols that have been used by surgeons. After the initial depletion of anterior keratocytes, keratocyte density seems to return to average 6-12 months after surgery when corneas are examined with the confocal microscope.

Assessment of the mechanical forces applied during eye rubbing.

BACKGROUND: To determine the average amount of mechanical forces applied to the lids of keratoconus patients during eye rubbing. METHODS: Fifty-seven patients (41 male, 16 female, average age 34.8 years) with a clinically and topographically diagnosed keratoconus and a history of eye rubbing were prospectively asked to perform their individual eye rubbing movement on a high-precision balance. The type of eye-rubbing movement and the force applied, represented in newtons (N), were recorded and analyzed. RESULTS: We detected three different types of eye rubbing. Rubbing with the fingertip was most frequent (51%), followed by rubbing with the knuckle (44%) and rubbing with the fingernail (6%). Each type of eye rubbing showed different average forces, with knuckle type eye rubbing applying significantly more force (9.6 ± 6.3 N) on the lids than fingertip (4.3 ± 3.1 N) and fingernail (2.6 ± 3.3 N) types (p < 0,001 and p = 0,016, respectively). CONCLUSIONS: There were major variations in the force exerted on the lids, depending on the type of eye rubbing employed. This data will help determine the forces that need to be applied in future experimental eye rubbing models.

Distinguishing Highly Asymmetric Keratoconus Eyes Using Combined Scheimpflug and Spectral-Domain OCT Analysis.

PURPOSE: To determine optimal objective, machine-derived variables and variable combinations from Scheimpflug and spectral-domain (SD) OCT imaging to distinguish the clinically unaffected eye in patients with asymmetric keratoconus (AKC) from a normal control population. DESIGN: Retrospective case-control study. PARTICIPANTS: Thirty clinically unaffected eyes with no physical findings on slit-lamp examination, no definitive abnormalities on corneal imaging, and corrected distance acuity of 20/20 or better from 30 patients with highly AKC eyes and 60 eyes from 60 normal control patients who had undergone uneventful LASIK with at least 2 years of stable follow-up (controls). METHODS: Scheimpflug and SD OCT imaging were obtained in all eyes, and receiver operating characteristic (ROC) curves were generated to determine area under the curve (AUC), sensitivity, and specificity for each machine-derived variable and variable combination. MAIN OUTCOME MEASURES: Distinguishing AKC eyes from controls as determined by AUC, sensitivity, and specificity. RESULTS: No individual machine-derived metric from Scheimpflug or SD OCT technology yielded an AUC higher than 0.75. Combining 5 Scheimpflug metrics (index height decentration [IHD], index vertical asymmetry [IVA], pachymetry apex, inferior-superior value, and Ambrosio's Relational Thickness Maximum [ARTmax]) yielded the best Scheimpflug results (AUC 0.86, sensitivity 83%, specificity 83%). Combining 11 SD OCT thickness metrics (minimum-median, temporal outer, superior nasal outer, minimum, epithelium minimum-maximum, epithelial standard deviation, superior inner, superior outer, superior temporal outer, superior nasal inner, central) yielded the best SD OCT results (AUC 0.96, sensitivity 89%, specificity 89%). Combining 13 total Scheimpflug/SD OCT metrics yielded the best results overall (AUC 1.0, sensitivity 100%, specificity 100%). The most impactful variables in combined models included epithelial thickness variability and total focal corneal thickness variability from SD OCT and anterior curvature and topometric indices from Scheimpflug technology. No posterior corneal metrics were impactful in modeling. CONCLUSIONS: Individual machine-derived metrics from Scheimpflug and SD OCT imaging poorly distinguished normal eyes from minimally affected eyes from patients with highly AKC. Combined SD OCT metrics performed better than combined Scheimpflug metrics. Combining anterior curvature and asymmetry indices from Scheimpflug with regional total thickness and epithelial thickness variability metrics from SD OCT clearly distinguished the 2 populations. Posterior corneal indices were not useful in distinguishing populations.

Pain management after photorefractive keratectomy.

PURPOSE OF REVIEW: To review current concepts regarding the mechanisms of postoperative pain after photorefractive keratectomy (PRK) and review available treatment options. RECENT FINDINGS: Many clinical studies have established the safety and efficacy of different topical and systematic therapeutic agents and techniques for the treatment of postoperative pain after PRK, especially topical nonsteroidal anti inflammatory agents and oral nonsteroidal and narcotic medications. New therapeutic agents and techniques are continuously studied, introducing new agents and comparing teh efficacy of different regimens. Postoperative pain severity varies widely between patients, and no single strategy has been proven best for acute pain management. SUMMARY: To date, the literature supports the use of topical agents such as nonsteroidal anti-inflammatory medications (NSAIDs) and diluted topical anesthetics in combination with oral agents such as opiates and NSAIDs for acute pain management. The use of local agents and techniques is preferred due to their less significant side effect profile. The use of systemic opiate agents is reserved for breakthrough pain.

Intraocular lens calculations after laser vision correction.

PURPOSE OF REVIEW: This article describes different strategies for corneal measurements and/or intraocular lens (IOL) calculations and proposes a systematic approach for IOL selection in patients who have undergone laser corneal refractive surgery. RECENT FINDINGS: Corneal measurements and IOL calculations cannot be obtained accurately with the standard measuring technologies and formulas in patients with history of laser corneal refractive surgery; therefore a variety of methods and formulas, some of which required prerefractive surgery data, have been proposed to improve the accuracy of measurements and calculations. Formulas that do not rely on prerefractive data seem to be as accurate as those that do; therefore the lack of prerefractive data no longer presents an obstacle for accurate IOL selection in these patients. SUMMARY: Postrefractive patients undergoing cataract extraction and IOL implantation should have corneal measurements and IOL calculations that take into account and compensate for the limitations in accurate measurements and calculations. IOL selection should also aim to compensate for induced spherical aberration according to the ablation pattern.

Intraocular lens alignment methods.

PURPOSE OF REVIEW: This article reviews current concepts in intraocular lens alignment strategies to maximize intraocular lens (IOL) positioning. RECENT FINDINGS: A variety of strategies has been developed to maximize toric IOL position, including preoperative calculators to determine the appropriate IOL power and orientation, intraoperative alignment devices, and postoperative software to determine if IOL rotation would be beneficial for refractive outcomes. SUMMARY: The combination of using multiple toric IOL calculators and intraoperative alignment devices has improved toric IOL outcomes. The relationship of the posterior corneal power and its effect on outcomes remains to be fully elucidated. Postoperative IOL rotation may be necessary even when the IOL is aligned as planned because of surgically induced astigmatism.

Therapeutic flap amputation for atypical LASIK flap and interface abnormalities.

PURPOSE: To describe LASIK flap amputation as a therapeutic option for patients with atypical refractory flap complications. METHODS: Case series and literature review. RESULTS: Seven eyes of 6 patients underwent flap amputation for various atypical indications, including non-infectious flap/interface opacity (3 patients), irregular astigmatism on the flap surface (3 patients), and chronic pain (concurrent in 2 patients with irregular astigmatism). In each case, conservative measures were ineffective. All patients had symptomatic improvement and improved corrected visual function after amputation; however, uncorrected distance visual acuity worsened in 2 patients, manifest refraction worsened in 3 patients, and irregular astigmatism increased in 2 patients. CONCLUSIONS: Flap amputation is a reasonable alternative to improve corrected acuity in select cases with significant flap opacities or irregular astigmatism unresponsive to conservative measures, but uncorrected acuity and irregular astigmatism may worsen and should be discussed during the informed consent process.

Role of percent tissue altered on ectasia after LASIK in eyes with suspicious topography.

PURPOSE: To investigate the association of the percent tissue altered (PTA) with the occurrence of ectasia after LASIK in eyes with suspicious preoperative corneal topography. METHODS: This retrospective comparative case-control study compared associations of reported ectasia risk factors in 129 eyes, including 57 eyes with suspicious preoperative Placido-based corneal topography that developed ectasia after LASIK (suspect ectasia group), 32 eyes with suspicious topography that remained stable for at least 3 years after LASIK (suspect control group), and 30 eyes that developed ectasia with bilateral normal topography (normal topography ectasia group). Groups were subdivided based on topographic asymmetry into high- or low-suspect groups. The PTA, preoperative central corneal thickness (CCT), residual stromal bed (RSB), and age (years) were evaluated in univariate and multivariate analyses. RESULTS: Average PTA values for normal topography ectasia (45), low-suspect ectasia (39), high-suspect ectasia (36), low-suspect control (32), and high-suspect control (29) were significantly different from one another in all comparisons (P < .003) except high- and low-suspect ectasia groups (P = .033), and presented the highest discriminative capability of all variables evaluated. Age was only significantly different between the high-suspect ectasia and normal topography ectasia groups, and CCT was not significantly different between any groups. Stepwise logistic regression revealed the PTA as the most significant independent variable (P < .0001), with RSB the next most significant parameter. CONCLUSIONS: There remains a significant correlation between PTA values and ectasia risk after LASIK, even in eyes with suspicious corneal topography. Less tissue alteration, or a lower PTA value, was necessary to induce ectasia in eyes with more remarkable signs of topographic abnormality, and PTA provided better discriminative capabilities than RSB for all study populations.

Current and future applications of corneal cross-linking.

PURPOSE OF REVIEW: To review current concepts and future directions of corneal cross-linking (CXL) as a treatment for keratoconus, ectasia after refractive surgery and infectious keratitis. RECENT FINDINGS: Several important laboratory and clinical studies have established the safety and success of corneal cross-linking for the treatment of keratoconus and other corneal ectasias. Recently, additional studies have analyzed new directions and controversies in corneal cross-linking, exploring new indications, comparing new techniques and analyzing results of new protocols. SUMMARY: The results of bench and clinical research are providing the foundation to allow for protocol modifications of the standard cross-linking protocols and expansion of cross-linking concepts for techniques such as accelerated cross-linking, epithelium-sparing protocols and measurement of progression and success.

Corneal collagen cross-linking (CXL) combined with refractive procedures for the treatment of corneal ectatic disorders: CXL plus.

PURPOSE: To discuss current combined corneal collagen cross-linking (CXL) and refractive surgical techniques (herein termed "CXL plus") for the treatment of corneal ectatic disorders to improve functional visual acuity in addition to corneal stability from CXL alone. METHODS: Literature review. RESULTS: Efficacious combined treatments with CXL include: photorefractive keratectomy, transepithelial phototherapeutic keratectomy, intrastromal corneal ring segments implantation, phakic intraocular lens implantation, and multiple combined procedures. Some uncertainty remains as to the optimal strategies for each patient. A decision tree is proposed to facilitate optimal patient management. CONCLUSIONS: With multiple adjuvant techniques, CXL plus is likely to benefit many patients with corneal ectatic disorders. The appropriate combined procedure will depend on multiple factors, such as refraction, corneal thickness, and degree of irregular astigmatism.

Epithelial and stromal remodeling after corneal collagen cross-linking evaluated by spectral-domain OCT.

PURPOSE: To evaluate changes in corneal epithelial and stromal thickness after corneal collagen cross-linking (CXL) in eyes with keratoconus and postoperative corneal ectasia using spectral-domain optical coherence tomography (SD-OCT). METHODS: Anterior segment SD-OCT (RTVue-100; Optovue, Inc., Fremont, CA) was used to compare regional corneal epithelial and stromal thickness in eyes with keratoconus and ectasia before CXL and 1 and 3 months after CXL. The anterior surface of the cornea, epithelium-Bowman's layer interface, and posterior reflective surface were used as anatomical landmarks to measure epithelial and stromal thickness, respectively. Regional thickness was assessed centrally and at 21 points 0.5 mm apart across the central 6 mm of the corneal vertex in the horizontal and vertical meridians. RESULTS: Thirty-one eyes from 30 patients were evaluated, including 17 eyes (17 patients) with keratoconus and 14 eyes (13 patients) with ectasia. Preoperatively, a highly irregular epithelial thickness profile and distribution was observed in both groups. After CXL, epithelial thickness was significantly thinner 2.5 and 2 mm below and 1.5 mm above the corneal apex (49.26 ± 5.69 µm; range: 43 to 62 µm), and 2.5 and 1 mm nasal and 2 mm temporal to the corneal apex (46.66 ± 4.53 µm; range: 39 to 57 µm) compared to preoperative values (P < .05 for all measurements). Epithelial thickness standard deviations were significantly lower (by 3 to 6 µm) 3 months after CXL, compared to ranges before CXL in both the vertical and horizontal meridians for keratoconus and ectasia (P = .048). No significant differences were found between epithelial remodeling in keratoconus and corneal ectasia (P = .98). No significant or consistent stromal changes were found for either group. CONCLUSIONS: Significant epithelial remodeling occurs after CXL in eyes with keratoconus and corneal ectasia, creating a similar, more regularized thickness profile in all meridians in the early postoperative period. This pattern of remodeling may facilitate interpretation of corneal curvature and thickness changes after CXL and may be related to visual acuity after CXL.

Transepithelial iontophoresis corneal collagen cross-linking for progressive keratoconus: initial clinical outcomes.

PURPOSE: To report initial clinical results of transepithelial corneal collagen cross-linking with iontophoresis (I-CXL). METHODS: Twenty eyes of 20 patients diagnosed as having progressive keratoconus who underwent I-CXL were included in this prospective non-randomized clinical study. Corrected distance visual acuity (CDVA), spherical equivalent and cylinder refraction, various corneal topography and Scheimpflug tomography parameters, aberrometry, anterior segment optical coherence tomography, and endothelial cell count were assessed at baseline and at 1, 3, 6, and 12 months postoperatively. RESULTS: CDVA improved significantly at 3, 6, and 12 months postoperatively (logMAR difference of -0.07 ± 0.01, -0.09 ± 0.03, and -0.12 ± 0.06, respectively; P < .05). Aberrometry remained stable during follow-up and a trend toward improvement was noted. All topographic parameters (including maximum keratometry) were stable during the follow-up, but exhibited a positive non-significant trend toward improvement. Minimum corneal thickness values were stable for up to 12 months postoperatively. None of the patients showed a progression of keratoconus. Endothelial cell counts did not change significantly (P > .05). CONCLUSIONS: Preliminary results up to 1 year postoperatively indicate the efficacy of I-CXL in stabilizing the progression of this degenerative disease combined with significant improvement of CDVA. I-CXL, which spares the corneal epithelium, has the potential to become a valid alternative for halting the progression of keratoconus while reducing postoperative patient pain, risk of infection, and treatment time in select patients; however, the relative efficacy of this technique compared to standard epithelium-off techniques remains to be determined.

Effects of corneal cross-linking on ocular response analyzer waveform-derived variables in keratoconus and postrefractive surgery ectasia.

PURPOSE: To assess changes in Ocular Response Analyzer (ORA) waveforms after UVA/riboflavin corneal collagen cross-linking (CXL) using investigator-derived and manufacturer-supplied morphometric variables in patients with keratoconus (KC) and postrefractive surgery ectasia. DESIGN: Prospective randomized trial of a standard epithelium-off CXL protocol. PARTICIPANTS: Patients with progressive KC (24 eyes of 21 patients) or postrefractive surgery ectasia (27 eyes of 23 patients) were enrolled. METHODS: Replicate ORA measurements were obtained before and 3 months after CXL. Pretreatment and posttreatment waveform variables were analyzed for differences by paired Student t tests using measurements with the highest waveform scores. MAIN OUTCOME MEASURES: Corneal hysteresis, corneal resistance factor, 37-s generation manufacturer-supplied ORA variables, and 15 investigator-derived ORA variables. RESULTS: No variables were significantly different 3 months after CXL in the KC group, and no manufacturer-supplied variables changed significantly in the postrefractive surgery ectasia group. Four custom variables (ApplanationOnsetTime, P1P2avg, Impulse, and Pmax) increased by small but statistically significant margins after CXL in the postrefractive surgery ectasia group. CONCLUSIONS: Changes in a small subset of investigator-derived variables suggested an increase in corneal bending resistance after CXL. However, the magnitudes of these changes were low and not commensurate with the degree of clinical improvement or prior computational estimates of corneal stiffening in the same cohort over the same period. Available air-puff-derived measures of the corneal deformation response underestimate the biomechanical changes produced by CXL.