David L DeMill

Ocular surface disease in patients with diabetic peripheral neuropathy

Purpose To analyse clinical signs and symptoms of ocular surface disease in patients with diabetes mellitus (DM), based on severity of diabetic peripheral neuropathy (DPN). Methods This cross-sectional study included participants who were carefully phenotyped by a multidisciplinary team and categorised into groups based on severity of DPN. All study participants underwent ophthalmic evaluation and completed the Ocular Surface Disease Index (OSDI) and Visual Function Questionnaire (VFQ-25). Results The 34 study participants were healthy controls (n=9), patients with DM and mild or no DPN (n=16) and patients with DM and severe DPN (n=9). Tear osmolarity was increased, and corneal nerve fibre length was decreased, with increasing severity of DPN. In addition, patients with DM were found to have decreased Schirmers test values when compared with healthy controls. No statistically significant differences were found between groups in OSDI, tear breakup time or corneal sensitivity. No statistically significant correlations were noted between the OSDI or VFQ-25 scores and clinical signs of dry eyes. Conclusion This study demonstrates some increased clinical signs of ocular surface disease but not an increase in subjective symptoms of dry eyes, with increasing severity of DPN. Furthermore, no significant correlation was found between OSDI scores and clinical signs of dry eye. A periodic evaluation of the ocular surface is important for patients with DM, in addition to retinopathy screening, as they may be asymptomatic but have severe dry eye disease, which can lead to further ocular surface complications such as corneal ulceration. Trial registration number NCT01695629.

Prevalence of Antiretinal Antibodies in Acute Zonal Occult Outer Retinopathy: A Comprehensive Review of 25 Cases

PURPOSE To perform a comprehensive review and to investigate the presence and role of autoimmune antibodies in 25 cases of acute zonal occult outer retinopathy (AZOOR) identified using the classification originally proposed by J. Donald Gass. DESIGN Observational case series. METHODS Setting: Institutional. STUDY POPULATION Twenty-five patients were identified by characteristic symptoms (abrupt onset of photopsias, followed by large scotomata at or connected to the blind spot), ocular findings (paucity of pigmentary changes with no sign of vitreous inflammation and abnormal electroretinogram in at least 1 eye), and a negative family history for retinitis pigmentosa. OBSERVATION PROCEDURES Patients underwent a full comprehensive ophthalmologic examination, fundus retinography, Goldmann kinetic visual field (GVF), and full-field electroretinogram (ffERG). Blood samples were also obtained to verify for the presence of antiretinal antibodies by Western blot analysis. MainOutcome Measures: Clinical presentation, best-corrected visual acuity (BCVA), fundus abnormalities, visual field defects, ffERG changes, and presence of antiretinal antibodies. RESULTS Sixteen patients (64%) presented with photopsias, 56% (14/25) with night blindness, and 56% (14/25) with loss of peripheral vision. Sixty-four percent (16/25) of cases were bilateral. All patients demonstrated retinal vascular attenuation, optic nerve head pallor, and mottling of retinal pigment epithelium. The most common visual field changes included enlargement and expansion of the blind spot extending into large pericentral or other types of scotomata (64%). Both scotopic and photopic ffERG values were abnormal and affected to a similar degree in our patients. Nine patients (36%) had a greater than 20% asymmetry in ERG values between the 2 eyes. All patients had antiretinal antibodies on Western blot with an average of 6.6 bands. CONCLUSION Evidence suggests that AZOOR is a unique form of autoimmune retinopathy and retinal manifestation suggests possible antiretinal antibody leakage from the disc margin with spread of immune products under the retina, resulting in large scotomata that connect to the optic nerve head.

Upper limits of intraocular pressure in glaucoma clinical trials.

Purpose: To determine the association of the lower limit of intraocular pressure (IOP) specified in the inclusion criteria to baseline and active treatment visit IOPs for monotherapy treatments. Methods: A review of clinical trial articles evaluating currently used topical glaucoma medicines. Articles were published between January 1995 and December 2011. Results: This study included 37 monotherapy treatment arms from 15 studies. There were 18 prostaglandin analogs, 8 b-blockers, 8 carbonic anhydrase inhibitors, 2 a-agonists, and 1 unoprostone. For all studies included generally there was a stepwise increase in the baseline 8 AM and diurnal IOP of approximately 1 mm Hg for each 1 mm Hg increase in entry criteria. This was true for all treatment arms together, with or without a PM entry criterion (P < 0.0001). However, the inclusion of an afternoon entry criterion time point did not seem to affect average IOP at baseline for the 8 AM and diurnal IOP. The treated reductions from baseline were not statistically different based on morning or afternoon entry criteria for either the 8 AM or diurnal IOPs (PZ0.07). Conclusions: Progressively higher 8 AM entry criteria IOPs at untreated baseline may influence, depending on design, in a linear manner the 8 AM and diurnal baseline IOPs of glaucoma studies at baseline. However, this effect was not observed in the treated reductions from baseline. Further, the addition of an afternoon entry criterion time point does not seem to change baseline 8 AM and diurnal IOPs.

Average versus Highest Intraocular Pressure Analyses in Glaucoma Clinical Trials

Purpose: To evaluate methods which account for both eyes as a single, independent variable in glaucoma clinical trials. Methods: A review of clinical trial articles published between January 1995 and April 2011 evaluating currently used topical glaucoma medications. Results: This analysis included 17 articles with 36 treatment arms of which 14 were prostaglandins, 13 β-blockers, 6 topical carbonic anhydrase inhibitors and 3 α-agonists. Twenty-four articles used average intraocular pressure (IOP) analysis, 12 used the highest IOP analysis and none utilized the randomized eye method. At untreated baseline, there was a difference in the IOP between average IOP and highest baseline IOP analyses at 8 a.m. (p = 0.001) and for the diurnal curve (p = 0.02) as well as specifically for β-blockers (p = 0.002) at 8 a.m. and β-blockers for the diurnal curve (p = 0.01). Conclusions: This study suggests that the highest IOP analysis method generally provides slightly higher IOPs at baseline than the average IOP analysis method.

Review of the influence of pigment dispersion and exfoliation glaucoma diagnosis on intraocular pressure in clinical trials evaluating primary open-angle glaucoma and ocular hypertension.

Purpose:To evaluate published, randomized, prospective, parallel clinical trials utilizing currently approved glaucoma medications to determine what influence, if any, pigment dispersion (PD) or exfoliation glaucoma (XFG) patients had on the intraocular pressure. Methods:A review of clinical trial articles evaluating currently used topical glaucoma medicines. Articles were published between January 1995 and April 2011. If the articles met the inclusion/exclusion criteria, they were analyzed for PD and XFG. Results:Twenty-four articles were included, containing 49 treatment arms that included PD or XFG patients. The range of PD patients was 0% to 4.5%, with a mean of 1.5±0.9%, and for XFG patients 0% to 6.3%, with a mean of 2.2±2.1%. The treatment arms with PD showed a difference in the intraocular pressures (IOPs), for all studies analyzed together, for the baseline IOPs between clinical trials that did and did not include PD patients (8 AM IOPs: with PD 26.5±0.9 mm Hg and without PD 25.8±1.3 mm Hg, P=0.024; and diurnal curve mean IOPs: with PD 25.3±1.1 mm Hg and without PD 24.5±1.3 mm Hg, P=0.024). The XFG treatment arms showed that there was a difference in the IOPs for all studies analyzed together for diurnal baseline IOPs between clinical trials that did and did not include XFG patients (with XFG 25.2±1.2 mm Hg and without XFG 24.3±1.0 mm Hg, P=0.016). Conclusions:Trial designs for prospective, parallel, glaucoma clinical studies that are performed in the United States generally can include PD and XFG patients with only a small impact on the IOP and a low number of such subjects enrolled.

Quantitative Analysis of Endothelial Cell Loss in Preloaded Descemet Membrane Endothelial Keratoplasty Grafts

Purpose: Availability of preloaded Descemet membrane endothelial keratoplasty (pDMEK) tissue may increase acceptance of DMEK in surgical management of endothelial disease. The goal of this study was to determine the safety of pDMEK grafts for 24 hours before surgery by analyzing endothelial cell loss (ECL) using 2 image analysis software programs. Methods: A total of 18 cadaveric corneas were prepared for DMEK using a standardized technique and loaded in a modified Jones tube injector. Nine of the corneas were injected into Calcein AM vital dye after 1 minute (controls), and the remaining 9 corneas were left preloaded for 24 hours before injection into vital dye for staining. The stained corneas were imaged using an inverted confocal microscope. ECL was then analyzed and quantified by 2 different graders using 2 image analysis software programs. Results: The control DMEK tissue resulted in 22.0% ± 4.0% ECL compared with pDMEK tissue, which resulted in 19.2% ± 7.2% ECL (P = 0.31). Interobserver agreement was 0.93 for MetaMorph and 0.92 for Fiji. The average time required to process images with MetaMorph was 2 ± 1 minutes and with Fiji was 20 ± 10 minutes. Intraobserver agreement was 0.97 for MetaMorph and 0.93 for Fiji. Conclusions: Preloading DMEK tissue is safe and may provide an alternative technique for tissue distribution and surgery for DMEK. The use of MetaMorph software for quantifying ECL is a novel and accurate imaging method with increased efficiency and reproducibility compared with the previously validated Fiji.