Radha P. Kohly

Antibiotic Resistance of Ocular Surface Flora With Repeated Use of a Topical Antibiotic After Intravitreal Injection

IMPORTANCE Treatment with intravitreal (IVT) injections has increased during the last several years as evidence has accumulated demonstrating the efficacy of anti-vascular endothelial growth factor agents in the treatment of neovascular age-related macular degeneration (AMD) and various retinal vascular diseases. Although IVT injections are generally safe, infectious endophthalmitis is a rare but devastating complication, and the risk of morbidity and vision loss from endophthalmitis is high. OBJECTIVE To examine the change in antibiotic resistance of ocular surface flora with repeated prophylactic use of antibiotics after IVT injection for AMD. DESIGN AND SETTING Prospective, nonrandomized cohort study in 2 tertiary academic hospitals. PARTICIPANTS Patients 65 years and older with newly diagnosed AMD were recruited by 7 retinal specialists from July 1, 2010, through December 31, 2011. INTERVENTION The study group received topical moxifloxacin hydrochloride for 3 days after each monthly IVT injection. MAIN OUTCOME MEASURE Resistance to moxifloxacin and ceftazidime in cultured isolates at baseline and monthly for 3 months by change in minimal inhibitory concentration (MIC) of culture isolates was studied. RESULTS The study group consisted of 84 patients, and the control group had 94 patients. In the study group, the baseline adjusted MIC increased (from 1.04 to 1.25 μg/mL; P = .01) as did the MIC for 50% of isolates (MIC50) (from 0.64 to 1.00 μg/mL) and the MIC for 90% of isolates (MIC90) (from 0.94 to 4.00 μg/mL). In both groups, the culture-positive rate did not change significantly when adjusted for baseline. No significant change was found in the MIC level, culture-positive rate, MIC50 level, and MIC90 level in the control group. Subgroup analysis found diabetes mellitus to be noncontributory to both the MIC and culture-positive rate. No endophthalmitis or adverse events were reported. CONCLUSIONS AND RELEVANCE Repeated use of topical moxifloxacin after IVT injection significantly increases antibiotic resistance of ocular surface flora. We recommend that routine use of prophylactic antibiotics after IVT injection be discouraged. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01181713.

Prospective Study of Inflammatory Biomarkers and Risk of Diabetic Retinopathy in the Diabetes Control and Complications Trial

IMPORTANCE This study demonstrates that increasing quintiles of baseline high-sensitivity C-reactive protein (hsCRP) level may be associated with higher risk of incident clinically significant macular edema, the leading cause of vision loss in working-aged individuals in North America. OBJECTIVE To determine whether baseline levels of hsCRP and intercellular adhesion molecule 1 (ICAM-1) predict development and progression of diabetic retinopathy (DR), clinically significant macular edema (CSME), retinal hard exudates, and proliferative DR in the Diabetes Control and Complications Trial (DCCT) cohort. DESIGN The DCCT was a large multicenter randomized controlled clinical trial. SETTING Twenty-nine medical centers in the United States and Canada. PARTICIPANTS The DCCT population consisted of 1441 subjects with type 1 diabetes mellitus aged 13 to 39 years at study entry. INTERVENTION We measured levels of hsCRP, ICAM-1, vascular cell adhesion molecule 1, and tumor necrosis factor α receptor 1 in stored baseline blood samples. MAIN OUTCOME MEASURES We assessed the association of levels of hsCRP, ICAM-1, vascular cell adhesion molecule 1, and tumor necrosis factor α receptor 1 with incident DR end points ascertained from grading of standardized 7-field stereoscopic retinal color photographs taken at baseline and every 6 months during follow-up. RESULTS After adjustment for randomized treatment assignment and other factors, we observed a statistically significant association between hsCRP and risk of CSME, with a relative risk (RR) for the top vs bottom quintile of 1.83 (95% CI, 0.94-3.55; P for trend = .01). Similarly, for the development of retinal hard exudates, the RR for the top vs bottom quintile of hsCRP level was 1.78 (95% CI, 0.98-3.25; P for trend = .004), whereas for ICAM-1 level, the RR comparing the top vs bottom quintiles was 1.50 (95% CI, 0.84-2.68; P for trend = .05). There were no statistically significant associations between baseline VCAM-1 or tumor necrosis factor α receptor 1 levels and risk of any of the DR end points. CONCLUSIONS AND RELEVANCE After adjusting for known risk factors, increasing quintiles of baseline hsCRP level may be associated with higher risk of incident CSME and macular hard exudate in the DCCT cohort. Circulating levels of ICAM-1 may also be associated with the development of retinal hard exudates.

Retinoschisis Detected With Handheld Spectral-Domain Optical Coherence Tomography in Neonates With Advanced Retinopathy of Prematurity

OBJECTIVES The recent development of handheld spectral-domain optical coherence tomography (HHSD-OCT) has enabled us to obtain high-resolution retinal scans of premature infants with retinopathy of prematurity (ROP). The purpose of this study is to document HHSD-OCT findings in laser-treated neonates with progressive ROP. METHODS This is a retrospective consecutive case series of 3 patients with progressive ROP despite laser photocoagulation. All patients were transferred from peripheral neonatal intensive care units (NICUs) to the Childrens Hospital Los Angeles. All patients had a complete ocular examination, fundus photography, fluorescein angiography, and HHSD-OCT. RESULTS All 3 patients had active progressive ROP despite prior laser photocoagulation. Of the 6 eyes, 1 was excluded from the study because it had an exudative retinal detachment following laser photocoagulation. Retinal detachment was not detected on clinical examination in the 5 remaining eyes, although there was vitreoretinal traction at the ridges of 3 of the 5 eyes. The HHSD-OCT identified presumed retinoschisis in all 5 study eyes. CONCLUSIONS Tractional retinoschisis may be an important finding in progressive laser-treated ROP, made possible by use of the HHSD-OCT. This finding may have significant implications for how we classify and treat patients whose ROP is progressing despite laser treatment. Furthermore, the use of the HHSD-OCT can provide valuable insight into the interaction of the retina, vitreous, and ridge in patients with progressive ROP, and it allows shallow detachments and retinoschisis to be diagnosed earlier and more accurately than would otherwise be possible.

Hand-held spectral domain optical coherence tomography finding in shaken-baby syndrome.

Purpose: The purpose of this study was to document the hand-held spectral domain optical coherence tomography (HHSD-OCT, Bioptigen, Durham, NC) findings in shaken-baby syndrome (SBS). The nonaccidental trauma in SBS has been associated with retinal findings, including hemorrhages in all layers of the retina and retinoschisis. Methods: Three consecutive patients with presumed SBS underwent complete ocular examination, fundus photography with the RetCam (Clarity Medical Systems, Pleasanton, CA), and imaging with the HHSD-OCT. Acquisition of the HHSD-OCT images required an assistant to stabilize the head of the infant. Results: All three patients had clinical findings consistent with SBS, including preretinal and intraretinal hemorrhages. Hand-held spectral domain optical coherence tomography documented focal posterior vitreous separation in four of the five eyes with multilayered retinoschisis in one eye, disruption of the foveal architecture and foveolar detachment in one eye, and disinsertion of the internal limiting membrane or inner retinoschisis in one eye. Hand-held spectral domain optical coherence tomography documented preretinal hemorrhages in all five eyes. Conclusion: Hand-held spectral domain optical coherence tomography is helpful in the evaluation of patients with SBS. All patients in our series had vitreoretinal abnormalities not detected on clinical examination, including, for example, multilayered retinoschisis. Hand-held spectral domain optical coherence tomography allows high-resolution imaging of the vitreoretinal interface and retina in infants with SBS and has provided insight into the mechanism of various retinal findings.

Management of pediatric choroidal neovascular membranes with intravitreal anti-VEGF agents: a retrospective consecutive case series

OBJECTIVE To report the results of pediatric choroidal neovascular membranes (CNVMs) secondary to a variety of etiologies treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents. DESIGN Retrospective case series. PARTICIPANTS Four pediatric patients at the Hosptial for Sick Children with CNVMs secondary to a variety of etiologies. METHODS Each patient received multiple treatments with one of the following anti-VEGF agents: pegaptanib sodium, bevacizumab, or ranibizumab. Progress was monitored by clinical exam, optical coherence tomography (OCT), and fluorescein angiography. RESULTS The mean age of our patients was 11.5 years (range, 8-15 years). Patients were followed for a mean of 10 months (range, 4-14 months). One patient was treated with pegaptanib sodium, 2 with bevacizumab, and 1 with ranibizumab. Following treatment, 1 patient showed an improvement and 3 showed stabilization of vision with reduction of fluid on clinical exam and OCT, and cessation of leakage on the fluorescein angiogram. Patients required 2-5 injections of the anti-VEGF agent. No ocular or systemic adverse events were observed in any of our treated patients. CONCLUSIONS Anti-VEGF agents were effective in the treatment of pediatric CNVMs in this case series. However, we do not know how these results would have differed from other treatment modalities, including observation. We did not observe any adverse side effects; however, larger studies are required to document the safety of these medications in the pediatric population where normal angiogenesis is occurring.

AQUEOUS HUMOR CYTOKINE LEVELS AS BIOMARKERS OF DISEASE SEVERITY IN DIABETIC MACULAR EDEMA.

Purpose: To determine whether aqueous cytokine levels correlate with disease severity in diabetic macular edema. Methods: A prospective cross-sectional study of 49 adults with diabetes mellitus, centre-involving diabetic macular edema and central subfield macular thickness ≥310 &mgr;m on spectral domain optical coherence tomography. Clinical examination and aqueous sampling were carried out before an initial injection of ranibizumab. Multiplex immunoassay of sample was carried out for vascular endothelial growth factor, placental growth factor, transforming growth factor beta, intercellular adhesion molecule-1, interleukin (IL)-2, IL-3, IL-6, IL-8, IL-10, IL-17, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, and epidermal growth factor. Multivariate robust regression models were constructed, and adjusted for age, lens status, or severity of retinopathy, and size of foveal avascular zone. Results: Spectral domain optical coherence tomography macular volume was an excellent measure of disease severity, correlating strongly with central subfield macular thickness (P < 0.001), best-corrected Snellen visual acuity (P < 0.001), and baseline diabetic retinopathy severity (P = 0.01). Elevated aqueous intercellular adhesion molecule-1 correlated with greater macular volume (P = 0.002). No aqueous cytokine, including VEGF, correlated with central subfield macular thickness. There was an association between IL-10 levels and best-corrected Snellen visual acuity (P = 0.03). Conclusion: Aqueous intercellular adhesion molecule-1 correlates with disease severity as measured by macular volume on spectral domain optical coherence tomography, and IL-10 is associated with BCVA. Intercellular adhesion molecule-1 may be a clinically useful biomarker for diabetic macular edema severity.

Aqueous Humor Cytokine Levels and Anatomic Response to Intravitreal Ranibizumab in Diabetic Macular Edema

Importance Variability in response to anti–vascular endothelial growth factor (VEGF) treatment in diabetic macular edema (DME) remains a significant clinical challenge. Biomarkers could help anticipate responses to anti-VEGF therapy. Objectives To investigate aqueous humor cytokine level changes in response to intravitreal ranibizumab therapy for the management of DME, and to determine the association between baseline aqueous levels and anatomic response. Design, Setting, and Participants In this prospective multicenter cohort study, 49 participants with diabetes mellitus complicated by center-involving DME, with a central subfield thickness of 310 &mgr;m or greater on spectral-domain optical coherence tomography (SD-OCT), were recruited from December 22, 2011, to June 13, 2013 and statistical analysis were performed from March 1, 2017, to June 1, 2017. A total of 48 participants proceeded to follow-up. Interventions Participants received monthly injections of ranibizumab, 0.5 mg, for 3 months. Aqueous fluid for cytokine analysis was obtained at baseline and repeated at the 2-month visit. Multiplex immunoassay was carried out in duplicate for VEGF, placental growth factor, transforming growth factor beta 2, intercellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), IL-8, IL-10, vascular intercellular adhesion molecule, and monocyte chemoattractant protein 1. Main Outcomes and Measures Baseline and 2-month change in aqueous cytokine levels, 3-month change in SD-OCT central subfield thickness and macular volume (MV), and the statistical association between baseline aqueous cytokine levels and these measures of anatomic response to ranibizumab in center-involving DME. Results Among the 48 participants, the mean (SD) age was 61.9 (7.1) years and 36 participants (75.0%) were men. The following cytokines were lower at month 2 vs baseline: ICAM-1 (median change, −190.88; interquartile range [IQR], −634.20 to −26.54; P < .001), VEGF (median change, −639.45; IQR, −1040.61 to −502.61; P < .001), placental growth factor (median change, −1.31; IQR, −5.99 to −0.01; P < .001), IL-6 (median change, −38.61; IQR, −166.72 to −2.80; P < .001), and monocyte chemoattractant protein 1 (median change, −90.13; IQR, −382.74 to 109.47; P = .01). When controlling for age, foveal avascular zone size, and severity of retinopathy, multiple linear regression determined that increasing baseline aqueous ICAM-1 was associated with a favorable anatomic response, in terms of reduced SD-OCT MV at 3 months (every additional 100 pg/mL of baseline ICAM-1 was associated with a reduction of 0.0379 mm3; P = .01). Conversely, increasing baseline aqueous VEGF was associated with a less favorable SD-OCT MV response at 3 months (every additional 100 pg/mL of baseline VEGF was associated with an increase of 0.0731 mm3; P = .02) and was associated with lower odds of being a central subfield thickness responder (odds ratio, 0.868; 95% CI, 0.755-0.998). Conclusions and Relevance Elevated aqueous ICAM-1 and reduced VEGF levels at baseline are associated with a favorable anatomic response to ranibizumab in DME, although there is not always direct correlation between anatomic and visual acuity response.

Referral characteristics and wait times for uveitis consultation at academic tertiary care centres in Toronto

OBJECTIVE To assess the characteristics of referrals to academic uveitis tertiary care centres in Toronto and identify determinants of wait time for consultation. DESIGN Retrospective case series. METHODS Consecutive new uveitis referrals received at 5 University of Toronto-affiliated uveitis tertiary care centres, between February 2016 and November 2016, were included. RESULTS A total of 159 new uveitis referrals were received from academic (69%) and community (31%) providers. A large proportion of referrals were sent by comprehensive ophthalmologists (33%) and retina specialists (38%). Disease was bilateral in 46% of cases, had an acute onset in 43% of cases, and was classified as posterior uveitis in 38% of cases. Disease etiology at the time of referral was unknown in 55% of cases. Only 43% of all referrals included a basic uveitis workup, and patients who had undergone diagnostic testing had a shorter wait time for consultation (41 ± 43 vs. 59 ± 54 days, p = 0.033). Acute uveitis had a shorter wait time compared with recurrent and chronic uveitis (33 ± 42 vs. 66 ± 44 and 59 ± 58 days, p < 0.001). Referrals triaged as urgent had significantly shorter wait times compared with referrals triaged as semiurgent or elective (7 ± 10 vs. 54 ± 43 and 88 ± 59, p < 0.001). CONCLUSIONS Referrals to academic uveitis tertiary care centres in Toronto are often acute, bilateral cases affecting the posterior segment without a known etiology. Approximately half of referrals include no diagnostic workup, which may delay diagnosis for patients and lengthen wait times for consultation. We provide a set of recommendations for investigations that should be included in uveitis referrals.

Age-related macular degeneration: Is polypoidal choroidal vasculopathy recognized and treated?

OBJECTIVE To assess how polypoidal choroidal vasculopathy (PCV) is recognized and treated, and to assess whether treatment outcomes are different between Chinese and Caucasian Canadian patients with age-related macular degeneration (AMD). DESIGN Retrospective chart review. PARTICIPANTS 154 eyes from 135 Chinese patients and 2291 eyes from 1792 Caucasian patients who were newly diagnosed with either AMD or PCV and had more than 1 year of follow-up were included. METHODS All newly diagnosed AMD patients presenting to the Retina Service of 3 Toronto University Hospitals, between March 25, 2008, to September 30, 2014, were reviewed. RESULTS 10/154 eyes (6.5%) in Chinese Canadians and 16/2291 eyes (0.7%) in Caucasian Canadians were diagnosed as having PCV. Indocyanine green angiography (ICGA) was used to diagnose PCV in 20% of Chinese Canadians and 8.8% of Caucasian Canadians. Clinical practices with a larger percentage of Chinese patients were more likely to diagnose PCV in both Chinese (p = 0.004) and Caucasian patients (p = 0.03), were more likely to use photodynamic therapy (PDT) (p < 0.01), and had significantly greater central retinal thickness decrease (p < 0.001). CONCLUSION Our study has shown that PCV is under-recognized in a Canadian population, and ICGA is underutilized. In clinical practices with a greater portion of Chinese patients, PCV is more often recognized and PDT is used more liberally.