Rohit Varma

Global prevalence and major risk factors of diabetic retinopathy

OBJECTIVE To examine the global prevalence and major risk factors for diabetic retinopathy (DR) and vision-threatening diabetic retinopathy (VTDR) among people with diabetes. RESEARCH DESIGN AND METHODS A pooled analysis using individual participant data from population-based studies around the world was performed. A systematic literature review was conducted to identify all population-based studies in general populations or individuals with diabetes who had ascertained DR from retinal photographs. Studies provided data for DR end points, including any DR, proliferative DR, diabetic macular edema, and VTDR, and also major systemic risk factors. Pooled prevalence estimates were directly age-standardized to the 2010 World Diabetes Population aged 20–79 years. RESULTS A total of 35 studies (1980–2008) provided data from 22,896 individuals with diabetes. The overall prevalence was 34.6% (95% CI 34.5–34.8) for any DR, 6.96% (6.87–7.04) for proliferative DR, 6.81% (6.74–6.89) for diabetic macular edema, and 10.2% (10.1–10.3) for VTDR. All DR prevalence end points increased with diabetes duration, hemoglobin A1c, and blood pressure levels and were higher in people with type 1 compared with type 2 diabetes. CONCLUSIONS There are approximately 93 million people with DR, 17 million with proliferative DR, 21 million with diabetic macular edema, and 28 million with VTDR worldwide. Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with DR. These data highlight the substantial worldwide public health burden of DR and the importance of modifiable risk factors in its occurrence. This study is limited by data pooled from studies at different time points, with different methodologies and population characteristics.

Detection of Macular Ganglion Cell Loss in Glaucoma by Fourier-Domain Optical Coherence Tomography

PURPOSE To map ganglion cell complex (GCC) thickness with high-speed Fourier-domain optical coherence tomography (FD-OCT) and compute novel macular parameters for glaucoma diagnosis. DESIGN Observational, cross-sectional study. PARTICIPANTS One hundred seventy-eight participants in the Advanced Imaging for Glaucoma Study, divided into 3 groups: 65 persons in the normal group, 78 in the perimetric glaucoma group (PG), and 52 in the preperimetric glaucoma group (PPG). METHODS The RTVue FD-OCT system was used to map the macula over a 7 x 6 mm region. The macular OCT images were exported for automatic segmentation using software we developed. The program measured macular retinal (MR) thickness and GCC thickness. The GCC was defined as the combination of nerve fiber, ganglion cell, and inner plexiform layers. Pattern analysis was applied to the GCC map and the diagnostic powers of pattern-based diagnostic parameters were investigated. Results were compared with time-domain (TD) Stratus OCT measurements of MR and circumpapillary nerve fiber layer (NFL) thickness. MAIN OUTCOME MEASURES Repeatability was assessed by intraclass correlation, pooled standard deviation, and coefficient of variation. Diagnostic power was assessed by the area under the receiver operator characteristic (AROC) curve. Measurements in the PG group were the primary measures of performance. RESULTS The FD-OCT measurements of MR and GCC averages had significantly better repeatability than TD-OCT measurements of MR and NFL averages. The FD-OCT GCC average had significantly (P = 0.02) higher diagnostic power (AROC = 0.90) than MR (AROC = 0.85 for both FD-OCT and TD-OCT) in differentiating between PG and normal. One GCC pattern parameter, global loss volume, had significantly higher AROC (0.92) than the overall average (P = 0.01). The diagnostic powers of the best GCC parameters were statistically equal to TD-OCT NFL average. CONCLUSIONS The higher speed and resolution of FD-OCT improved the repeatability of macular imaging compared with standard TD-OCT. Ganglion cell mapping and pattern analysis improved diagnostic power. The improved diagnostic power of macular GCC imaging is on par with, and complementary to, peripapillary NFL imaging. Macular imaging with FD-OCT is a useful method for glaucoma diagnosis and has potential for tracking glaucoma progression.

Retinal Nerve Fiber Layer Thickness in Normal Human Eyes

PURPOSE To measure the histologic thickness of the retinal nerve fiber layer (RNFL) in normal human eyes. METHODS Human eyes were obtained at autopsy within 6 hours postmortem. The retina was dissected into four quadrants and serially sectioned in historesin. The RNFL thickness was measured histologically in all four quadrants at the disc margin and at regular intervals from the disc margin. Measurements of the RNFL thickness also were obtained at the fovea and in the retinal periphery. RESULTS Ten eyes of ten white individuals were studied. Age (mean +/- standard deviation) was 53.1 +/- 19.6 years (range, 18-76 years). For the eyes studied, the disc area (mean +/- standard deviation) and cup:disc ratio (mean +/- standard deviation) were 1.92 +/- 0.1 mm2 and 0.3 +/- 0.08, respectively. Mean superior, inferior, nasal, and temporal RNFL thickness at the disc margin was 405, 376, 372, and 316 microns, respectively. In all four quadrants, the RNFL thickness decreased with increasing distance from the disc margin. The average superior and inferior RNFL thickness was inversely related to age (P = 0.033, P = 0.097, respectively). The average RNFL thickness was not related to disc area. The average RNFL thickness just superior, inferior, nasal, and temporal to the foveola was 27, 34, 26, and 12 microns, respectively. The average RNFL thickness just posterior to the ora serrata in the superior, inferior, nasal, and temporal retinal periphery was 8 to 11 microns. CONCLUSION The peripapillary RNFL thickness in humans is thicker than that seen in nonhuman primates. The thinnest peripapillary RNFL is in the region of the papillomacular bundle. These data can be used to determine the accuracy of NFL analyzers in obtaining in vivo RNFL thickness measurements.

Wireless Intraocular Pressure Sensing Using Microfabricated Minimally Invasive Flexible-Coiled LC Sensor Implant

This paper presents an implant-based wireless pressure sensing paradigm for long-range continuous intraocular pressure (IOP) monitoring of glaucoma patients. An implantable parylene-based pressure sensor has been developed, featuring an electrical LC-tank resonant circuit for passive wireless sensing without power consumption on the implanted site. The sensor is microfabricated with the use of parylene C (poly-chloro-p-xylylene) to create a flexible coil substrate that can be folded for smaller physical form factor so as to achieve minimally invasive implantation, while stretched back without damage for enhanced inductive sensor-reader coil coupling so as to achieve strong sensing signal. A data-processed external readout method has also been developed to support pressure measurements. By incorporating the LC sensor and the readout method, wireless pressure sensing with 1-mmHg resolution in longer than 2-cm distance is successfully demonstrated. Other than extensive on-bench characterization, device testing through six-month chronic in vivo and acute ex vivo animal studies has verified the feasibility and efficacy of the sensor implant in the surgical aspect, including robust fixation and long-term biocompatibility in the intraocular environment. With meeting specifications of practical wireless pressure sensing and further reader development, this sensing methodology is promising for continuous, convenient, direct, and faithful IOP monitoring.

Intraocular pressure control and long-term visual field loss in the collaborative initial glaucoma treatment study

OBJECTIVE To evaluate the impact of measures of intraocular pressure (IOP) control on progression of visual field (VF) loss during long-term treatment for open-angle glaucoma (OAG). DESIGN Longitudinal, randomized clinical trial. PARTICIPANTS We included 607 participants with newly diagnosed OAG. METHODS Study participants were randomly assigned to initial treatment with medications or trabeculectomy, and underwent examination at 6-month intervals. Standardized testing included Goldmann applanation tonometry and Humphrey 24-2 full threshold VFs. Summary measures of IOP control during follow-up included the maximum, mean, standard deviation (SD), range, proportion less than 16, 18, 20, or 22 mmHg, and whether all IOP values were less than each of these 4 cutpoints. Predictive models for VF outcomes were based on the mean deviation (MD) from VF testing, and were adjusted for age, gender, race, baseline VF loss, treatment, and time. Each summary IOP measure was included as a cumulative, time-dependent variable, and its association with subsequent VF loss was assessed from 3 to 9 years postrandomization. Both linear mixed models, to detect shifts in MD levels, and logistic models, to detect elevated odds of substantial worsening (≥3 dB), were used. MAIN OUTCOME MEASURES We measured the MD from Humphrey 24-2 full threshold VF tests. RESULTS The effect of the summary IOP measures differed between the medicine and surgery groups in models that addressed the continuous MD outcome. After adjustment for baseline risk factors, in the medicine group larger values of 3 IOP control measures-maximum IOP (P = 0.0003), SD of IOP (P = 0.0056), and range of IOP (P<0.0001)-were significantly associated with lower (worse) MD over the 3- to 9-year period. No IOP summary measure was significantly associated with MD over time in the surgery group. The same 3 IOP summary measures were also significantly associated with substantial worsening of MD; however, the effects were similar in both treatment groups. In models predicting inadequate IOP control, consistently significant predictors of higher maximum, SD, and range of IOP included black race, higher baseline IOP, and clinical center. CONCLUSIONS These results support considering more aggressive treatment when undue elevation or variation in IOP measures is observed.

Agreement among Optometrists, Ophthalmologists, and Residents in Evaluating the Optic Disc for Glaucoma

PURPOSE To determine the agreement among optometrists, ophthalmologists, and ophthalmology residents in assessing glaucomatous optic nerve damage. The authors also determined the sensitivity of each group of observers for identifying glaucomatous optic nerve damage. METHODS Six optometrists, six general ophthalmologists, and six third-year ophthalmology residents evaluated 75 stereoscopic optic disc photographs. Observers estimated the vertical cup:disc ratio (C:D) and assessed the presence of glaucomatous damage. Agreement among and within observers was estimated by the kappa statistic (KW, k). The sensitivity and specificity for the identification of glaucomatous optic nerve damage were determined for each group of participants. RESULTS Intraobserver agreement (KW 0.69-0.79) was greater than interobserver agreement (KW 0.56-0.68) in assessing the C:D ratio and glaucomatous optic nerve damage for optometrists, ophthalmologists, and residents. Interobserver agreement for ophthalmologists (KW 0.68) was substantial and significantly higher than for optometrists (KW 0.56) and residents (KW 0.56) when estimating the C:D ratio. Ophthalmologists and residents had higher sensitivity (78%) in identifying glaucomatous optic nerve damage than did optometrists (56%). The specificity for all three groups was relatively poor (range, 47%-60%). CONCLUSION The moderate interobserver agreement across all three groups of observers suggests the need to develop standardized criteria for assessing glaucomatous optic disc damage. Ophthalmologists in this study have a higher interobserver agreement in estimating the C:D ratio and are more sensitive than optometrists in assessing glaucomatous optic nerve damage.

Pilot study of optical coherence tomography measurement of retinal blood flow in retinal and optic nerve diseases

PURPOSE To investigate blood flow changes in retinal and optic nerve diseases with Doppler Fourier domain optical coherence tomography (OCT). METHODS Sixty-two participants were divided into five groups: normal, glaucoma, nonarteritic ischemic optic neuropathy (NAION), treated proliferative diabetic retinopathy (PDR), and branch retinal vein occlusion (BRVO). Doppler OCT was used to scan concentric circles of 3.4- and 3.75-mm diameters around the optic nerve head. Flow in retinal veins was calculated from the OCT velocity profiles. Arterial and venous diameters were measured from OCT Doppler and reflectance images. RESULTS Total retinal blood flow in normal subjects averaged 47.6 μL/min. The coefficient of variation of repeated measurements was 11% in normal eyes and 14% in diseased eyes. Eyes with glaucoma, NAION, treated PDR, and BRVO had significantly decreased retinal blood flow compared with normal eyes (P < 0.001). In glaucoma patients, the decrease in blood flow was highly correlated with the severity of visual field loss (P = 0.003). In NAION and BRVO patients, the hemisphere with more severe disease also had lower blood flow. CONCLUSIONS Doppler OCT retinal blood flow measurements showed good repeatability and excellent correlation with visual field and clinical presentations. This approach could enhance our understanding of retinal and optic nerve diseases and facilitate the development of new therapies.

Prevalence of refractive error in Singaporean Chinese children: the Strabismus, Amblyopia, and Refractive Error in Young Singaporean Children (STARS) Study.

PURPOSE To determine the prevalence of refractive error types in Singaporean Chinese children aged 6 to 72 months. METHODS The Strabismus, Amblyopia and Refractive Error in Singaporean Children (STARS) is a population-based study in southwest Singapore. Door-to-door recruitment of participants was used, with disproportionate random sampling in 6-month increments. Parental questionnaires were administered. Participant eye examinations included logMAR visual acuity, cycloplegic autorefraction, and ocular biometry. Overall and age-specific prevalences of myopia (spherical equivalence [SE] <or= -0.50 D), high myopia (SE <or= -6.00 D), hyperopia (SE >or= +3.00 D), astigmatism (cylinder >or= +1.50 D), and anisometropia (SE difference between each eye >or=2.00 D) were calculated. RESULTS A total of 3009 children were examined (participation rate, 72.3%). Right eye (OD) cycloplegia data were available for 1375 boys and 1264 girls (mean age, 41 months). Mean OD SE was +0.69 D (SD 1.15). Overall myopia prevalence was 11.0% with no variance between the sexes (P = 0.91). The prevalence of high myopia (at least -6.00 D) was 0.2%. The prevalences of hyperopia, astigmatism, and anisometropia were 1.4%, 8.6%, and 0.6%, respectively. Most astigmatism (>95%) was with-the-rule (cylinder axes between 1 degrees and 15 degrees or 165 degrees and 180 degrees ). Myopia was present in 15.8%, 14.9%, 20.2%, 8.6%, 7.6%, and 6.4% of children aged 6 to 11, 12 to 23, 24 to 35, 36 to 47, 48 to 59, and 60 to 72 months, respectively. Prevalence increased with age for astigmatism (P < 0.001), but not for hyperopia or anisometropia (P = 0.55 and P = 0.37), respectively. CONCLUSIONS The prevalences of myopia and astigmatism in young Singaporean Chinese children are high, but that of hyperopia is low. Age effects were observed for each refractive error category, but differences between the sexes were not significant. Age-related variation in myopia prevalence may be influenced by ocular development, environment, and/or testability.

Variation in optic nerve and macular structure with age and race with spectral-domain optical coherence tomography.

PURPOSE To evaluate the effects of age and race on optic disc, retinal nerve fiber layer (RNFL), and macular measurements with spectral-domain optical coherence tomography (SD OCT). DESIGN Cross-sectional observational study. PARTICIPANTS Three hundred fifty adult subjects without ocular disease. METHODS Data from SD OCT imaging of the optic nerve head, peripapillary RNFL, and macula of 632 eyes from 350 subjects without ocular disease were imaged with SD OCT. Multivariate models were used to determine the effect of age and race on quantitative measurements of optic disc, RNFL, and macula. MAIN OUTCOME MEASURES Optic nerve, RNFL, and macular measurements with SD OCT across racial strata and age. RESULTS For optic nerve parameters, participants of European descent had significantly smaller optic disc area than other groups (P<0.0001), and Indian participants had significantly smaller rim area than other groups (P<0.0001). Indian and Hispanic participants had thicker global RNFL measurements than other groups (P<0.0001). Participants of African descent were associated with thinner inner retinal thickness in the macula (P<0.0001). Age was associated with several parameters, with rim area reducing by 0.005 mm(2)/year, RNFL thickness reducing by 0.18 μm/year, and inner retinal thickness reducing by 0.1 μm/year (P<0.0001 for all age associations). CONCLUSIONS Optic nerve, RNFL, and macular measurements with SD OCT all varied across racial groups and with age. These differences are important in defining the range of normal variation in differing populations and should be considered in the use of these instruments in the detection of optic nerve and macular disease across these population groups. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Early Changes in Optic Disc Compliance and Surface Position in Experimental Glaucoma

PURPOSE To detect changes in the compliance and baseline position (position at the baseline time point of a compliance test) of the monkey optic disc after the onset of chronic experimental glaucoma. METHODS Sixty-six compliance tests were performed on 26 eyes of 13 monkeys. Longitudinal Study. In seven normal monkeys, compliance tests were performed three times in one eye (study eye) and once in the contralateral eye. In the study eye of five of these monkeys, chronic experimental glaucoma was then induced and compliance tests were performed at some or all of the following postglaucoma testing intervals: 1 to 2 weeks, 3 to 4 weeks, 5 to 8 weeks, 9 to 12 weeks, 13 to 18 weeks, and more than 18 weeks after the onset of elevated intraocular pressure (IOP). In the study eye of the remaining two monkeys, the optic nerve was transected, and compliance was tested at 5, 9, and 13 weeks after transection. An analysis of variance (ANOVA) was performed to detect an increase (hypercompliance) or decrease (rigidity) in the compliance of the glaucomatous eyes at each testing interval. A second ANOVA was performed to detect the onset of chronic posterior deformation of the baseline position of each disc. Cross-Sectional Study. In six additional monkeys with pre-existing experimental glaucoma, the glaucomatous study eye was compliance tested at one of the postglaucoma testing intervals used in the longitudinal study. The contralateral normal eye was compliance tested once. These data were then added to the data from the five longitudinally studied monkeys at the appropriate preglaucoma and postglaucoma testing intervals. A third ANOVA was done to compare the compliance of the expanded group of glaucomatous eyes at each postintervention testing interval with the compliance of the 13 normal contralateral eyes. RESULTS Compliance. In the longitudinally (Pr > F = 0.0005) and cross-sectionally (Pr > F = 0.0001) studied glaucomatous eyes, optic disc compliance increased significantly by 1 to 2 weeks and then returned to a level statistically indistinguishable from normal within 13 to 18 weeks after the onset of glaucoma. In the transection eyes, the optic discs were significantly less compliant (more rigid) at 5 and 9 weeks after transection compared with the discs in either the normal or the glaucomatous eyes (Pr > F < 0.05). Baseline Optic Disc Position. Chronic posterior deformation of the disc was detected in one of three eyes tested 1 to 2 weeks and three of four eyes tested 3 to 4 weeks after the onset of glaucoma (Pr > F < 0.05). Chronic posterior deformation was not detected in the discs of either of the transection eyes at any of the post-transection testing intervals. CONCLUSION Changes in optic disc compliance and surface position were detected by digitized image analysis within 2 to 4 weeks of the onset of experimental glaucoma in the monkey eye. These findings are unlikely to be due to axon loss alone, because they did not occur in optic nerve transection eyes (which constitute a model of axon loss in which intraocular pressures remain normal). The results suggest that IOP-related damage to the load-bearing connective tissues of the optic nerve head may occur early in the course of experimental glaucoma.