Joshua R. Ehrlich

Detection of retinal changes in Parkinson's disease with spectral-domain optical coherence tomography

Purpose This pilot study investigated whether high-resolution spectral-domain optical coherence tomography (SD-OCT) could detect differences in inner retinal layer (IRL), peripapillary retinal nerve fiber layer (RNFL), and macular thickness between patients with Parkinson’s disease (PD) and controls. Methods Both eyes of patients with PD and age-matched controls were imaged with the Heidelberg Spectralis® HRA + OCT. RNFL, IRL, and macular thickness were measured for each eye using Heidelberg software. These measurements were compared with validated, published normal values for macular and RNFL thickness, and compared with matched controls for IRL thickness. Results Eighteen eyes from nine subjects with PD and 19 eyes of 16 control subjects were evaluated using SD-OCT. The average age of PD patients was 64 years with a range of 52–75 years. The average age of controls was 67 years with a range of 50–81 years. No significant reduction in IRL thickness was detected between PD patients and age-matched controls at 13 points along a 6 mm horizontal section through the fovea. No significant difference in RNFL thickness was detected between PD patients and published normal values. Overall average RNFL thickness was 97 μm for PD patients, which exactly matched the normative database value. However, significant differences in macular thickness were detected in three of nine subfields between PD subjects and published normal values. In PD subjects, the outer superior subfield was 2.8% thinner (P = 0.026), while the outer nasal and inner inferior subfields were 2.8% (P = 0.016) and 2.7% (P = 0.001) thicker compared to published normal values. Conclusion In this pilot study, significant differences in macular thickness were detected in three of nine subfields by SD-OCT. However, SD-OCT did not detect significant reductions in peripapillary RNFL and IRL thickness between PD patients and controls. This suggests that macular thickness measurements by SD-OCT may potentially be used as an objective, noninvasive, and easily quantifiable in vivo biomarker in PD. Larger, longitudinal studies are needed to explore these relationships further.

Value of serum antisperm antibodies in diagnosing obstructive azoospermia.

PURPOSE The requisite presence of active spermatogenesis for antisperm antibody production may be useful in identifying obstructive azoospermia. The diagnostic performance of serum antisperm antibody was evaluated as a test for obstructive azoospermia. MATERIALS AND METHODS A total of 484 men with male infertility who had undergone antisperm antibody testing were evaluated. Demographic data, patient history, and followup were recorded. Obstruction was confirmed by surgical exploration. Sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios were calculated to quantify diagnostic performance. ROC curves were calculated and compared. RESULTS Of 484 men 272 possessed documented obstruction of the vas or epididymis and 212 had documented infertility without azoospermia. The obstructed group had significantly increased antisperm antibody levels compared to the nonobstructed group. IgG, IgA, and IgM were analyzed as diagnostic tests for obstruction. The AUC for IgG, IgA and IgM ROC curves was 0.92, 0.85 and 0.67, respectively. The AUC for serum IgG against sperm tails was 0.92, 0.87 against sperm heads and 0.79 against sperm midpieces. IgG demonstrated the highest sensitivity (85%) with a specificity of 97% (chi-square test p <0.01). IgA possessed the highest specificity (99%), positive predictive value (99%) and positive likelihood ratio (70.0). CONCLUSIONS The presence of serum antisperm antibody was highly accurate in predicting obstructive azoospermia, particularly after vasectomy. It can obviate the need for testis biopsy, the current but more invasive and costly gold standard of detection. This allows the surgeon to proceed directly to surgical reconstruction or sperm retrieval after a simple blood test.

Retinal nerve fiber layer evaluation in multiple sclerosis with spectral domain optical coherence tomography

Purpose: Histopathologic studies have reported retinal nerve fiber layer (RNFL) thinning in various neurodegenerative diseases. Attempts to quantify this loss in vivo have relied on time-domain optical coherence tomography (TDOCT), which has low resolution and requires substantial interpolation of data for volume measurements. We hypothesized that the significantly higher resolution of spectral-domain optical coherence tomography (SDOCT) would better detect RNFL changes in patients with multiple sclerosis, and that RNFL thickness differences between eyes with and without optic neuritis might be identified more accurately. Methods: In this retrospective case series, patients with multiple sclerosis were recruited from the Judith Jaffe Multiple Sclerosis Center at Weill Cornell Medical College in New York. Patients with a recent clinical diagnosis of optic neuritis (less than three months) were excluded. Eyes with a history of glaucoma, optic neuropathy (other than multiple sclerosis-related optic neuritis), age-related macular degeneration, or other relevant retinal and/or optic nerve disease were excluded. Both eyes of each patient were imaged with the Heidelberg Spectralis® HRA + OCT. RNFL and macular thickness were measured for each eye using the Heidelberg OCT software. These measurements were compared with validated published normal values, and were modeled as linear functions of duration of disease. The odds of an optic neuritis diagnosis as a function of RNFL and macular thickness were calculated. Results: Ninety-four eyes were prospectively evaluated using OCT. Ages of patients ranged from 26 to 69 years, with an average age of 39 years. Peripapillary RNFL thinning was demonstrated in multiple sclerosis patients; mean RNFL thickness was 88.5 μm for individuals with multiple sclerosis compared with a reported normal value of 97 μm (P < 0.001). Eyes with a history of optic neuritis had more thinning compared with those without optic neuritis (83.0 μm versus 90.5 μm, respectively, P = 0.02). No significant differences were observed in macular thickness measurements between eyes with and without optic neuritis, nor were macular thickness measurements significantly different from normal values. As a function of multiple sclerosis duration and controlling for age, RNFL thickness was decreased in patients with a duration of multiple sclerosis greater than five years compared with those with a duration less than or equal to one year (P = 0.008). Conclusions: Patients with a history of multiple sclerosis had RNFL thinning that was detectable on SDOCT. Decreasing RNFL thickness in eyes with optic neuritis was found, and the odds of having optic neuritis were increased significantly with decreasing RNFL thickness. Average RNFL thinning with increasing duration of disease was an excellent predictor of a reported history of optic neuritis. SDOCT retinal imaging may represent a high-resolution, objective, noninvasive, and easily quantifiable in vivo biomarker of the presence of optic neuritis and severity of multiple sclerosis.

The relationship between corneal hysteresis and the magnitude of intraocular pressure reduction with topical prostaglandin therapy

Aims To evaluate corneal hysteresis (CH) and intraocular pressure (IOP) before and after IOP lowering with prostaglandin analogue (PGA) therapy in medication-naïve eyes. Methods In this retrospective study, we included records from 57 consecutive patients with open angle glaucoma who were initiated on PGA. Patients underwent ocular response analyser measurement with IOP assessment at baseline (untreated) and at follow-up (treated). Results Median follow-up time between IOP measurements was 1.4 (range 0.4–13.5) months. IOP was reduced by 3.2 mm Hg (18.8%) from 17.0 to 13.8 mm Hg (p<0.001). CH increased by 0.5 mm Hg (5.2%) from 9.7 to 10.2 mm Hg (p=0.02). Baseline CH (but not baseline central corneal thickness) was a significant predictor of the magnitude of IOP reduction, with patients in the lowest quartile of CH (mean 7.0 mm Hg) experiencing a 29.0% reduction in IOP while those in the highest CH quartile (mean 11.9 mm Hg) experienced a 7.6% reduction in IOP (p=0.006). A multivariate analysis controlling for baseline IOP demonstrated that baseline CH independently predicted the magnitude of IOP reduction with PGA therapy in both per cent (ß=3.5, p=0.01) and absolute (ß=0.6, p=0.02) terms. Conclusion Although CH is influenced by IOP, baseline CH is independently associated with the magnitude of IOP reduction with PGA therapy.

Variation in corneal hysteresis and central corneal thickness among black, hispanic and white subjects

Purpose:  To determine whether differences in corneal hysteresis (CH) and central corneal thickness (CCT) between black, Hispanic and white subjects exist independently of one another.

Goldmann applanation tonometry compared with corneal-compensated intraocular pressure in the evaluation of primary open-angle Glaucoma

BackgroundTo better understand the role of corneal properties and intraocular pressure (IOP) in the evaluation of primary open-angle glaucoma (POAG); and to determine the feasibility of identifying glaucomatous optic neuropathy (GON) using IOP corrected and uncorrected for corneal biomechanics.MethodsRecords from 1,875 eyes of consecutively evaluated new patients were reviewed. Eyes were excluded if central corneal thickness (CCT) or Ocular Response Analyzer (ORA) measurements were unavailable. Presence or absence of GON was determined based on morphology of the optic disc, rim and retinal nerve fiber layer at the time of clinical examination, fundus photography and Heidelberg Retinal Tomography. Goldmann-applanation tonometry (GAT) in the untreated state was recorded and Goldmann-correlated (IOPg) and corneal-compensated IOP (IOPcc) were obtained using the ORA. Glaucomatous eyes were classified as normal or high-tension (NTG, HTG) using the conventional cutoff of 21 mm Hg. One eligible eye was randomly selected from each patient for inclusion.ResultsA total of 357 normal, 155 HTG and 102 NTG eyes were included. Among NTG eyes, IOPcc was greater than GAT (19.8 and 14.4 mm Hg; p < 0.001) and the difference between IOPcc and GAT was greatest for this subgroup of patients with NTG (p ≤ 0.01). The maximum combined sensitivity and specificity for detection of GON occurred at 20.9 mm Hg for GAT (59%, 90%) and 18.4 mm Hg for IOPcc (85%, 85%) and the area under the curve was greater for IOPcc (0.93 vs. 0.78; p < 0.001).ConclusionsIOPcc may account for measurement error induced by corneal biomechanics. Compared to GAT, IOPcc may be a superior test in the evaluation of glaucoma but is unlikely to represent an effective diagnostic test.

The role of clinical parapapillary atrophy evaluation in the diagnosis of open angle glaucoma

Purpose: To determine if clinical evaluation of parapapillary atrophy (PPA) significantly improves the ability to distinguish open-angle glaucoma (OAG) patients from glaucoma suspects. Methods: Patients in this study were under evaluation for glaucoma and had open angles, at least one reliable 24-2 SITA-standard automatic perimetry, and digital stereophotographs of the optic disc. PPA was identified clinically as a parapapillary region of absent (βPPA) or hyper/hypopigmented (αPPA) retinal pigment epithelium. A single masked observer evaluated photos for: vertical cup-to-disc ratio (CDR), clock hours of total and βPPA, βPPA as percentage width of the optic disc, presence or absence of βPPA at each disc quadrant, and ordinal rating of total PPA. Generalized linear models were used to determine odds of an abnormal or borderline glaucoma hemifield test (GHT) as a function of PPA variables and covariates; model fit was assessed using the log-likelihood ratio test. Results: Of 410 consecutive patients, 540 eyes (of 294 patients) met inclusion criteria. Mean age was greater among patients with abnormal compared with normal GHT (P < 0.001), but sex and race/ethnicity did not differ between groups (P ≥ 0.22). Age, central corneal thickness (CCT) and CDR (P ≤ 0.006), but not intraocular pressure (IOP) (P = 0.71), were significant univariable predictors of the odds of an abnormal GHT. All PPA parameters significantly predicted GHT (P ≤ 0.03), except presence of temporal βPPA (P = 0.25). Adjustment for age, CCT, IOP, and CDR reduced the association between PPA and GHT, and model fit was not greatly improved by addition of PPA variables. Conclusions: Addition of most PPA parameters to a model already containing commonly assessed variables including age, CCT, IOP, and CDR does not significantly improve the ability to distinguish OAG patients from glaucoma suspects.

A native antigen "reverse capture" microarray platform for autoantibody profiling of prostate cancer sera.

Cancer sera contain antibodies that react with autologous cellular antigens. Here, we report the use of a novel native antigen‐based platform, the “reverse capture” autoantibody microarray, for identification of autoantigens against which autoantibody expression may be used to differentiate between patients with prostate cancer and benign prostate hyperplasia (BPH). Serum samples were collected at our institution from patients with BPH and patients with prostate carcinoma with similar blood prostate‐specific antigen levels. IgG was purified from individual prostate cancer sera, differentially labeled with fluorescent dyes, and competitively hybridized against purified IgG from a group of well‐characterized BPH control patients on our reverse capture microarray platform. For each experiment, we performed a two‐slide dye‐swap. Using this platform, we identified 28 unique antigen‐autoantibody reactivities that have the potential to discriminate prostate cancer from BPH. These autoantigens, with p‐values ≤0.01, can be placed into the following general categories: protein kinases, cell‐cycle regulators, cancer‐growth factors, apoptosis mediators, and transcription factors. In addition, only 1 of the 28 autoantigens remained differentially targeted by autoantibodies in post‐surgical prostate cancer patients after a minimum 1‐year follow‐up. Autoantibody profiling using this platform may be a useful tool for differentiating between malignant and benign diseases of the prostate.

Change in corneal hysteresis over time in normal, glaucomatous and diabetic eyes

Corneal hysteresis (CH) is lower in glaucomatous eyes. The aim of this study was to determine and compare the change in CH over time between normal, open angle glaucoma (POAG) and diabetic subjects.

Autoantibody microarrays for biomarker discovery

Identification of autoantigens and the detection of autoantibody reactivity are useful in biomarker discovery and for explaining the role of important biochemical pathways in disease. Despite all of their potential advantages, the main challenge to working with autoantibodies is their sensitivity. Nevertheless, proteomics may hold the key to overcoming this limitation by providing the means to multiplex. Clearly, the ability to detect multiple autoantigens using a platform such as a high-density antigen microarray would improve sensitivity and specificity of detection for autoantibody profiling. The aims of this review are to: briefly describe the current status of antigen–autoantibody microarrays; provide examples of their use in biomarker discoveries; address current limitations; and provide examples and strategies to facilitate their implementation in the clinical setting.