Karun S. Arora

A versatile pH sensitive chondroitin sulfate–PEG tissue adhesive and hydrogel

We developed a chondroitin sulfate-polyethylene glycol (CS-PEG) adhesive hydrogel with numerous potential biomedical applications. The carboxyl groups on chondroitin sulfate (CS) chains were functionalized with N-hydroxysuccinimide (NHS) to yield chondroitin sulfate succinimidyl succinate (CS-NHS). Following purification, the CS-NHS molecule can react with primary amines to form amide bonds. Hence, using six arm polyethylene glycol amine PEG-(NH2)6 as a crosslinker we formed a hydrogel which was covalently bound to proteins in tissue via amide bonds. By varying the initial pH of the precursor solutions, the hydrogel stiffness, swelling properties, and kinetics of gelation could be controlled. The sealing/adhesive strength could also be modified by varying the damping and storage modulus properties of the material. The adhesive strength of the material with cartilage tissue was shown to be ten times higher than that of fibrin glue. Cells encapsulated or in direct contact with the material remained viable and metabolically active. Furthermore, CS-PEG material produced minimal inflammatory response when implanted subcutaneously in a rat model and enzymatic degradation was demonstrated in vitro. This work establishes an adhesive hydrogel derived from biological and synthetic components with potential application in wound healing and regenerative medicine.

The Choroid Is Thicker in Angle Closure than in Open Angle and Control Eyes

PURPOSE To study factors associated with choroidal thickness (CT) and to compare CT in angle closure (AC), open angle (OA), and normal eyes. METHODS Forty controls, 106 OA, and 79 AC subjects underwent measurements of posterior CT by spectral domain-optical coherence tomography, and of intraocular pressure (IOP), blood pressure, axial length (AL), and central corneal thickness (CCT). RESULTS CT was significantly greater in AC than in OA and normal eyes (HSD test, P ≤ 0.05), but there was no significant difference between OA and normal CT; mean CT was 234, 235, and 318 μm in the normal, OA, and AC groups, respectively. With multivariable analysis among all participants, thinner CT was associated with older age, longer AL, higher IOP, and thicker CCT (all P ≤ 0.03, R(2) = 0.45). Adjusting for other relevant variables, the AC group had a significantly greater CT than either the normal or the OA group (P = 0.003 and 0.03, respectively). In multivariable analysis including only OA and AC patients, neither cup-to-disc ratio nor visual field mean deviation were significantly associated with CT. Multivariable analysis for CT among normal eyes found longer AL to be associated with thinner CT (P = 0.04). CONCLUSIONS AC eyes had significantly thicker CT than OA and normal eyes, even after adjusting for the shorter AL in AC eyes, supporting hypotheses that choroidal expansion contributes to the development of AC disease. Age, AL, CCT, and IOP were also significantly associated with CT, while severity of glaucoma damage was not.

Use of Various Glaucoma Surgeries and Procedures in Medicare Beneficiaries from 1994 to 2012

PURPOSE Determine how procedural treatments for glaucoma have changed between 1994-2012. DESIGN Retrospective, observational analysis. PARTICIPANTS Medicare Part B beneficiaries. METHODS We analyzed Medicare fee-for-service paid claims data between 1994-2012 to determine the number of surgical/laser procedures performed for glaucoma in the Medicare population each year. MAIN OUTCOME MEASURES Number of glaucoma-related procedures performed. RESULTS Trabeculectomies in eyes without previous scarring decreased 52% from 54 224 in 1994 to 25 758 in 2003, and a further 52% to 12 279 in 2012. Trabeculectomies in eyes with scarring ranged from 9054 to 13 604 between 1994-2003, but then decreased 48% from 11 018 to 5728 between 2003-2012. Mini-shunts done via an external approach (including ExPRESS [Alcon Inc, Fort Worth, TX]) increased 116% from 2718 in 2009 to 5870 in 2012. The number of aqueous shunts to the extraocular reservoir increased 231% from 2356 in 1994 to 7788 in 2003, and a further 54% to 12 021 in 2012. Total cyclophotocoagulation procedures increased 253% from 2582 in 1994 to 9106 in 2003, and a further 54% to 13 996 in 2012. Transscleral cyclophotocoagulations decreased 45% from 5978 to 3268 between 2005-2012; over the same period, the number of endoscopic cyclophotocoagulations (ECPs) increased 99% from 5383 to 10 728. From 2001 to 2005, the number of trabeculoplasties more than doubled from 75 647 in 2001 to 176 476 in 2005, but since 2005 the number of trabeculoplasties decreased 19% to 142 682 in 2012. The number of laser iridotomies was fairly consistent between 1994-2012, increasing 9% over this period and ranging from 63 773 to 85 426. Canaloplasties increased 1407% from 161 in 2007 to 2426 in 2012. Between 1994-2012, despite a 9% increase in beneficiaries, the total number of glaucoma procedures and the number of glaucoma procedures other than laser procedures decreased 16% and 31%, respectively. CONCLUSIONS Despite the increase in beneficiaries, the number of glaucoma procedures performed decreased. Glaucoma procedures demonstrating a significant increase in use include canaloplasty, mini-shunts (external approach), aqueous shunt to extraocular reservoir, and ECP. Trabeculectomy use continued its long-term downward trend. The continued movement away from trabeculectomy and toward alternative intraocular pressure-lowering procedures highlights the need for well-designed clinical trials comparing these procedures.

Change in choroidal thickness and axial length with change in intraocular pressure after trabeculectomy

Background/aims We studied the change in choroidal thickness (CT) and axial length (AL) after intraocular (IOP) changes produced by trabeculectomy. Methods Twenty-one eyes of 20 patients were studied preoperatively, and then postoperatively at 1 week, 1, 3, and 6 months. Variables measured included IOP, AL, keratometry, refractive error, central corneal thickness, and average CT in the posterior 6 mm centred on the fovea using enhanced depth imaging spectral domain optical coherence tomography (OCT). Results OCT images in 17 eyes (58 images, preoperatively and postoperatively) were of sufficient quality to determine CT. In every patient, CT increased with IOP lowering postoperatively. For each 1 mm Hg decrease in IOP, there was a mean increase of 3.4 µm in CT (p<0.0001; univariate regression, 95% CI 2.5 to 4.3). This represented a CT increase of 1.7% per mm Hg decrease (p<0.0001; 95% CI 1.3 to 2.0%). AL decreased by 6.8 µm per mm Hg decrease in IOP (p<0.0001, univariate regression, 95% CI 4.9 to 8.6). Conclusions The dynamic relationship between change in IOP and the state of sclera and choroid was confirmed by sequential measurements in postoperative trabeculectomy patients, providing estimates of the magnitude of choroidal swelling and scleral volume decrease with IOP lowering.

The relationship between better-eye and integrated visual field mean deviation and visual disability.

OBJECTIVE To determine the extent of difference between better-eye visual field (VF) mean deviation (MD) and integrated VF (IVF) MD among Salisbury Eye Evaluation (SEE) subjects and a larger group of glaucoma clinic subjects and to assess how those measures relate to objective and subjective measures of ability/performance in SEE subjects. DESIGN Retrospective analysis of population- and clinic-based samples of adults. PARTICIPANTS A total of 490 SEE and 7053 glaucoma clinic subjects with VF loss (MD ≤-3 decibels [dB] in at least 1 eye). METHODS Visual field testing was performed in each eye, and IVF MD was calculated. Differences between better-eye and IVF MD were calculated for SEE and clinic-based subjects. In SEE subjects with VF loss, models were constructed to compare the relative impact of better-eye and IVF MD on driving habits, mobility, self-reported vision-related function, and reading speed. MAIN OUTCOME MEASURES Difference between better-eye and IVF MD and relationship of better-eye and IVF MD with performance measures. RESULTS The median difference between better-eye and IVF MD was 0.41 dB (interquartile range [IQR], -0.21 to 1.04 dB) and 0.72 dB (IQR, 0.04-1.45 dB) for SEE subjects and clinic-based patients with glaucoma, respectively, with differences of ≥ 2 dB between the 2 MDs observed in 9% and 18% of the groups, respectively. Among SEE subjects with VF loss, both MDs demonstrated similar associations with multiple ability and performance metrics as judged by the presence/absence of a statistically significant association between the MD and the metric, the magnitude of observed associations (odds ratios, rate ratios, or regression coefficients associated with 5-dB decrements in MD), and the extent of variability in the metric explained by the model (R(2)). Similar associations of similar magnitude also were noted for the subgroup of subjects with glaucoma and subjects in whom better-eye and IVF MD differed by ≥ 2 dB. CONCLUSIONS The IVF MD rarely differs from better-eye MD, and similar associations between VF loss and visual disability are obtained using either MD. Unlike better-eye MD, IVF measurements require extra software/calculation. As such, information from studies using better-eye MD can be more easily integrated into clinical decision-making, making better-eye MD a robust and meaningful method for reporting VF loss severity.

Increased choroidal thickness in patients with Sturge-Weber syndrome.

IMPORTANCE With the recent development of enhanced depth imaging spectral-domain optical coherence tomography (SD-OCT), it is now possible to measure choroidal thickness in patients with Sturge-Weber syndrome and detect abnormalities that are not visible as part of the fundus examination. OBSERVATIONS We were successful in imaging at least 1 eye in 12 individuals with Sturge-Weber syndrome using enhanced depth imaging SD-OCT. Eyes were defined as affected if they manifested at least one of the following: darkened choroid, glaucomatous optic nerve damage, or conjunctival hyperemia. None of the participants had a clinically visible choroidal hemangioma. The affected eyes had over twice the choroidal thickness of the unaffected eyes (mean [SD], 697 [337] μm vs 331 [94] μm; P = .004, determined by use of an unpaired t test). For the 6 unilaterally affected participants who had both eyes imaged, the choroidal thickness was greater in the affected eyes than in the unaffected eyes of 5 participants (mean [SD], 672 [311] μm vs 329 [88] μm; P = .01, determined by use of a paired t test). CONCLUSIONS AND RELEVANCE The advent of enhanced depth imaging SD-OCT has allowed us to quantify choroidal thickness in the posterior pole, even in eyes with a markedly thickened choroid, such as those found in individuals with Sturge-Weber syndrome. Spectral-domain OCT has a much higher resolution (5-10 μm) than B-scan ultrasonography (150 μm) and can be used to distinguish between the retina and the choroid. Furthermore, enhanced depth imaging SD-OCT can detect choroidal thickness in eyes without clinically apparent choroidal abnormalities.

Symmetry of the pupillary light reflex and its relationship to retinal nerve fiber layer thickness and visual field defect

PURPOSE To assess the relationship between the pupillary light reflex (PLR) and visual field (VF) mean deviation (MD) and retinal nerve fiber layer (RNFL) thickness. METHODS A total of 148 patients with glaucoma (mean age 67 ± 11, 49% female) and 71 controls (mean age 60 ± 10, 69% female) were included in this study. Using a pupillometer, we recorded and analyzed pupillary responses at varied stimulus patterns (full field, superonasal and inferonasal quadrant arcs). We compared the responses between the two eyes, compared responses to stimuli in the superonasal and inferonasal fields within each eye, and calculated the absolute PLR value of each individual eye. We assessed the relationship among PLR, MD, and RNFL thickness using the Pearson correlation coefficient. For analyses performed at the level of individual eyes, we used multilevel modeling to account for between-eye correlations within individuals. RESULTS For every 0.3 log unit difference in between-eye asymmetry of PLR, there was an average 2.6-dB difference in visual field MD (correlation coefficient R = 0.83, P < 0.001) and a 3.2-μm difference in RNFL thickness between the two eyes (R = 0.67, P < 0.001). Greater VF damage and thinner RNFL for each individual eye were associated with smaller response amplitude, slower velocity, and longer time to peak constriction and dilation after adjusting for age and sex (all P < 0.001). However, within-eye asymmetry of PLR between superonasal and inferonasal stimulation was not associated with corresponding within-eye differences in VF or RNFL. CONCLUSIONS As measured by this particular device, the PLR is strongly correlated with VF functional testing and measurements of RNFL thickness.

The effect of scleral spur identification methods on structural measurements by anterior segment optical coherence tomography.

Purpose:To assess methods for and variations in identifying the scleral spur (SS) position in anterior segment optical coherence tomography. Methods:In images of 51 eyes (patients) with open and closed anterior chamber angles, we compared the success rate and the variability of 3 approaches for identifying the SS: the ciliary muscle (CM), bump, and Schwalbe line (SL) methods using mixed effects regression models. The effect of incremental variation in SS position on anterior chamber parameters using the Anterior Segment Analysis Program (ASAP) was analyzed in 8 images. Automated ASAP measurements were compared with manual ImageJ measurements in 46 images. Results:The SS could be identified in 98% of images by each observer using the 3 methods in combination. The SL and CM approaches more successfully identified the SS (82% and 81% success, respectively) than the bump method (59%, P<0.001). The intraobserver, interobserver, and intermethod variabilities of the CM and bump methods were superior to those of the SL method. The SS was more likely to be identified in open angle than angle closure eyes (OR=2.26, P=0.03) and brown eyes were less likely than blue eyes (OR=0.36, P=0.04). Movement of SS position resulted in substantial differences in the angle parameters and iris concavity ratio, whereas iris area and volume were less affected. Conclusions:The CM method was the most successful and least variable method of SS marking, which was more difficult in narrow angle and brown eyes. Variability of SS placement had a large effect on angle parameters and iris concavity ratio.

Biomechanical Responses of Lamina Cribrosa to Intraocular Pressure Change Assessed by Optical Coherence Tomography in Glaucoma Eyes

Purpose The purpose of this study was to measure change in anterior lamina cribrosa depth (ALD) globally and regionally in glaucoma eyes at different intraocular pressures (IOP). Methods Twenty-seven glaucoma patients were imaged before and after IOP-lowering procedures using optical coherence tomography. The anterior lamina was marked in approximately 25 locations in each of six radial scans to obtain global and regional estimates of ALD. ALD and its change with IOP were compared with optic disc damage, nerve fiber layer thickness, and visual field loss. Results Variables associated with deeper baseline ALD included larger cup/disc ratio, thinner rim area, larger cup volume, thinner central corneal thickness, and male sex (all P ≤ 0.02). When IOP was lowered, ALD position became more anterior, more posterior, or was unchanged. The mean ALD change after lowering was 27 ± 142 μm (P = 0.3). The mean absolute value of ALD change was 112 ± 90 μm (P = 0.002). Change in ALD was greater in eyes with lower IOP in paired comparisons (P = 0.006) but was not associated with the magnitude of IOP lowering between imaging sessions (P = 0.94). Eyes with no significant change in ALD tended to have more visual field loss than those with significant anterior ALD displacement (P = 0.07). Areas within each optic nerve head that corresponded to zones with thicker nerve fiber layer had greater ALD positional change (P = 0.0007). Conclusions The lamina can move either anteriorly or posteriorly with IOP decrease, with greater displacement at lower IOP. Glaucoma eyes and regions within glaucoma eyes associated with greater glaucoma damage exhibited smaller responses.

Results From a Modified Bleb Needling Procedure With Continuous Infusion Performed in the Operating Room.

Purpose:Needling of a scarred trabeculectomy bleb is often performed in the office using a slit-lamp microscope as an alternative to additional surgery to lower intraocular pressure (IOP). However, the success rate in an office setting is highly variable, with reported success rates as low as 13%. We report a retrospective assessment of an intraoperative needling technique for reviving failed blebs. Design:A retrospective chart review. Participants:Patients undergoing the intraoperative modified bleb revision technique in the setting of a failed trabeculectomy due to scarring at the Wilmer Eye Institute, Johns Hopkins Hospital between August 16, 2010 and August 29, 2012. Methods:Patients with uncontrolled IOP were operated on using a modified bleb needling technique. In this technique, a 25-G infusion cannula is placed in the anterior chamber and fibrotic adhesions within the bleb are lysed with a 25-G needle. The continuous infusion of balanced salt solution from the anterior chamber causes bleb elevation, which helps to guide the endpoint of lysis for the procedure. A subconjunctival injection of 5-fluorouracil is given at the conclusion of each case. Main Outcome Measures:IOP reduction and number of glaucoma medications at postoperative day 1, week 1, month 1, month 3, month 6, and month 12. Results:A total of 33 eyes of 30 patients were included. At the visit before the procedure, the mean (±SD) IOP was 22.1±9.2 (range, 11 to 58) and subjects were using an average of 2.3±1.4 (range, 0 to 4) glaucoma medications. The mean IOP reduction was 8.7 mm Hg [95% confidence interval (CI), 5.6-11.8] at postoperative day 1, 8.1 mm Hg (95% CI, 4.0-12.3) at week 1, 8.9 mm Hg (95% CI, 5.3-12.5) at month 1, 8.1 mm Hg (95% CI, 4.2-12.0) at month 3, 8.2 mm Hg (95% CI, 3.9-12.5) at month 6, and 6.2 mm Hg (95% CI, 3.6-8.7) at month 12. IOP was reduced about 30% to 40% compared with baseline at each time point (P<0.05). The average reduction in medications used was 1.7 at day 1, 1.0 at month 1, 1.2 at month 3, 1.5 at month 6, and 0.5 at month 12. Seven patients underwent repeat needling. Overall, 64% of subjects maintained IOP at or below their target after 12 months. Conclusions:A modified bleb needling procedure performed in the operating room can successfully lower IOP in the setting of a previous trabeculectomy in over 60% of subjects a year after the procedure.