Rahul A. Jonas

Parapapillary Atrophy: Histological Gamma Zone and Delta Zone

Background To examine histomorphometrically the parapapillary region in human eyes. Methodology/Principal Findings The histomorphometric study included 65 human globes (axial length:21–37 mm). On anterior-posterior histological sections, we measured the distance Bruchs membrane end (BME)-optic nerve margin (“Gamma zone”), BME-retinal pigment epithelium (RPE) (“Beta zone”), BME-beginning of non-occluded choriocapillaris, and BME-beginning of photoreceptor layer. “Delta zone” was defined as part of gamma zone in which blood vessels of at least 50 µm diameter were not present over a length of >300 µm. Beta zone (mean length:0.35±0.52 mm) was significantly (P = 0.01) larger in the glaucoma group than in the non-glaucomatous group. It was not significantly (P = 0.28) associated with axial length. Beta zone was significantly (P = 0.004) larger than the region with occluded choriocapillaris. Gamma zone (mean length:0.63±1.25 mm) was associated with axial length (P<0.001;r2 = 0.73) with an increase starting at an axial length of 26.5 mm. It was not significantly (P = 0.24) associated with glaucomatous optic neuropathy. Delta zone (present only in eyes with axial length of ≥27 mm) was associated with axial length (P = 0.001) and scleral flange length (P<0.001) but not with glaucoma (P = 0.73). Conclusions/Significance Parapapillary gamma zone (peripapillary sclera without overlying choroid, Bruchs membrane and deep retinal layers) was related with axial globe elongation and was independent of glaucoma. Delta zone (no blood vessels >50 µm diameter within gamma zone) was present only in highly axially elongated globes and was not related with glaucoma. Beta zone (Bruchs membrane without RPE) was correlated with glaucoma but not with globe elongation. Since the region with occluded choriocapillaris was smaller than beta zone, complete loss of RPE may have occurred before complete choriocapillaris closure.

Histology of the Parapapillary Region in High Myopia

PURPOSE To examine histomorphometrically the parapapillary region in highly myopic eyes. DESIGN Retrospective laboratory investigation. METHODS We examined a highly myopic glaucomatous group (36 human globes; axial length >26.5 mm) and a non-highly myopic group (28 globes with secondary angle-closure glaucoma; 17 eyes with malignant choroidal melanoma). Using light microscopy, pupil-optic nerve sections were assessed. RESULTS The length of the scleral flange (sclera between optic nerve border and optic nerve dura mater) increased with axial length (P < .001; correlation coefficient r = 0.70) and decreased with its thickness (P < .001; r = 0.75). In all highly myopic eyes (n = 15) with a distance of >0.5 mm between optic nerve border and beginning of Bruch membrane, the parapapillary region consisted of an elongated parapapillary scleral flange associated with a scleral flange thinning and a retrobulbar cerebrospinal fluid space extended into the retroparapapillary region. The parapapillary retina was composed of retinal nerve fiber layer (or its remnants) only, without elements of any other retinal layer, without underlying Bruch membrane or choroid. These histologic features were not detected in any of the non-highly myopic eyes. CONCLUSIONS Since parapapillary scleral thickness influences the lamina cribrosa biomechanics, the findings may partially explain the increased glaucoma susceptibility in highly myopic eyes. The implications of an absence of Bruch membrane and choroid in the highly myopic parapapillary region, and the implications of the retrobulbar parapapillary extension of the cerebrospinal spinal fluid space for the pathophysiology of the optic nerve head, have to be elucidated.

The Spider Effect: Morphological and Orienting Classification of Microglia in Response to Stimuli in Vivo

The different morphological stages of microglial activation have not yet been described in detail. We transected the olfactory bulb of rats and examined the activation of the microglial system histologically. Six stages of bidirectional microglial activation (A) and deactivation (R) were observed: from stage 1A to 6A, the cell body size increased, the cell process number decreased, and the cell processes retracted and thickened, orienting toward the direction of the injury site; until stage 6A, when all processes disappeared. In contrast, in deactivation stages 6R to 1R, the microglia returned to the original site exhibiting a stepwise retransformation to the original morphology. Thin highly branched processes re-formed in stage 1R, similar to those in stage 1A. This reverse transformation mirrored the forward transformation except in stages 6R to 1R: cells showed multiple nuclei which were slowly absorbed. Our findings support a morphologically defined stepwise activation and deactivation of microglia cells.

Cytokine concentration in aqueous humor of eyes with diabetic macular edema.

Purpose: To measure cytokine concentrations in aqueous humor of eyes with diffuse diabetic macular edema. Methods: The interventional clinical comparative study included a study group of 23 patients with diffuse diabetic macular edema and a control group of 22 patients undergoing cataract surgery. Cytokine concentrations were measured in aqueous humor samples using a Luminex xMAP suspension array technology. Results: In the study group as compared with the control group, significantly higher concentrations were measured for epidermal growth factor (P < 0.001), human growth factor (P < 0.001), intercellular adhesion molecule-1 (ICAM-1; P < 0.001), interleukin (IL)-1a2 (P = 0.04), IL-6 (P = 0.001), IL-8 (P < 0.001), interferon gamma–induced protein (P = 0.004), monocyte chemoattractant protein-1 (P < 0.001), monokine induced by interferon gamma (P < 0.001), matrix metalloproteinase 1 (P = 0.02), matrix metalloproteinase 9 (P < 0.001), plasminogen activator inhibitor 1 (P < 0.001), placenta growth factor (P < 0.001), tissue growth factor beta (P = 0.003), vascular cell adhesion molecule (P < 0.001), and vascular endothelial growth factor (P < 0.001). Retinal macula thickness was significantly associated with the concentrations of the epidermal growth factor (P = 0.005; &rgr; = 0.45), ICAM-1 (P < 0.001; &rgr; = 0.65), IL-3 (P = 0.002; &rgr; = 0.48), IL-6 (P = 0.003; &rgr; = 0.47), IL-8 (P < 0.001; &rgr; = 0.71), monocyte chemoattractant protein-1 (P = 0.001; &rgr; = 0.53), monokine induced by interferon gamma (P < 0.001; &rgr; = 0.57), matrix metalloproteinase 9 (P < 0.001; &rgr; = 0.61), tissue growth factor beta (P = 0.01; &rgr; = 0.42), placenta growth factor (P = 0.004; &rgr; = 0.46), vascular cell adhesion molecule (P = 0.006; &rgr; = 0.44), and vascular endothelial growth factor (P = 0.01; &rgr; = 0.42). In multivariate analysis, macular thickness remained to be significantly associated with the concentration of ICAM-1 (P = 0.03; r = 0.30). Vascular endothelial growth factor concentrations were correlated with concentration of placenta growth factor (P < 0.001; &rgr; = 0.78), plasminogen activator inhibitor 1 (P = 0.001; &rgr; = 0.54), ICAM-1 (P < 0.001; &rgr; = 0.47), monokine induced by interferon gamma (P = 0.004; &rgr; = 0.44), monocyte chemoattractant protein-1 (P = 0.003; &rgr; = 0.43), vascular cell adhesion molecule (P = 0.01; &rgr; = 0.38), IL-6 (P = 0.02; &rgr; = 0.35), IL-8 (P = 0.02; &rgr; = 0.37), epidermal growth factor (P = 0.01; &rgr; = 0.39), and macrophage migration inhibitory factor (P = 0.01; &rgr; = 0.37). Conclusion: Numerous cytokines are associated with the presence and the amount of diabetic macular edema. Among these cytokines, ICAM-1 was the most significantly associated with the disease parameters.

Parapapillary Gamma Zone and Axial Elongation–Associated Optic Disc Rotation: The Beijing Eye Study

PURPOSE The parapapillary gamma zone has been defined as the parapapillary region without Bruchs membrane. We examined which morphologic parameters are associated with the presence and size of the parapapillary gamma zone. METHODS Using fundus photographs and spectral-domain optical coherence tomographic images of the optic nerve head in the population-based Beijing Eye Study, we determined parapapillary gamma zone width, macular Bruchs membrane length, optic disc-fovea distance, the angle of horizontal optic disc rotation, the angle of vertical optic disc rotation, and the ratio of the vertical-to-horizontal disc diameter. RESULTS The study included 2068 individuals with a mean age of 63.0 ± 9.0 years (range, 50-91 years), and mean axial length was 23.2 ± 1.0 mm (range, 18.96-28.87 mm). In multivariate analysis, larger width of parapapillary gamma zone was associated with more marked vertical optic disc rotation (P < 0.001; standardized correlation coefficient β, 0.15; nonstandardized correlation coefficient B, 0.02; 95% confidence interval [CI], 0.02, 0.03), more marked horizontal optic disc rotation (P = 0.02; β, 0.05; B, 0.01; 95% CI, 0.001, 0.01), longer axial length (P = 0.01; β, 0.07; B, 0.02; 95% CI, 0.01, 0.04), longer horizontal optic disc diameter (P = 0.02; β, 0.05; B, 0.06; 95% CI, 0.01, 0.12), longer disc-fovea distance (P < 0.001; β, 0.25; B, 0.22; 95% CI, 0.18, 0.27), higher degree of fundus tessellation (P = 0.03; β, 0.17; B, 0.04; 95% CI, 0.03, 0.0), and thinner subfoveal choroidal thickness (P < 0.001; β, -0.13; B, 0.000; 95% CI, -0.001, 0.000). Parapapillary gamma zone width was not significantly associated with macular Bruchs membrane length (P = 0.72), disc-fovea angle (P = 0.62), age (P = 0.62), or sex (P = 0.46). CONCLUSIONS The parapapillary gamma zone was associated with an axial elongation-induced rotation of the optic disc mainly around the vertical disc axis, leading to a stretching of the temporal peripapillary scleral flange. Because macular Bruchs membrane length was independent of axial elongation, it leaves the temporal parapapillary region with an uncovered Bruchs membrane (i.e., parapapillary gamma zone develops).

Optic Disc - Fovea Distance, Axial Length and Parapapillary Zones. The Beijing Eye Study 2011

Purpose To measure the distance between the optic disc center and the fovea (DFD) and to assess its associations. Methods The population-based cross-sectional Beijing Eye Study 2011 included 3468 individuals aged 50+ years. The DFD was measured on fundus photographs. Results Readable fundus photographs were available for 2836 (81.8%) individuals. Mean DFD was 4.76 ± 0.34mm (median: 4.74 mm; range: 3.76–6.53mm). In multivariate analysis, longer DFD was associated with longer axial length (P<0.001; standardized correlation coefficient beta: 0.62), higher prevalence of axially high myopia (P<0.001; beta:0.06), shallower anterior chamber depth (P<0.001; beta:-0.18), thinner lens thickness (P = 0.004; beta: -0.06), smaller optic disc-fovea angle (P = 0.02; beta: -0.04), larger parapapillary alpha zone (P = 0.008; beta: 0.05), larger parapapillary beta/gamma zone (P<0.001; beta: 0.11), larger optic disc area (P<0.001; beta: 0.08), lower degree of cortical cataract (P = 0.002; beta: -0.08), and lower prevalence of age-related macular degeneration (P = 0.001; beta: -0.06). Bruch´s membrane opening-fovea distance (DFD minus disc radius minus parapapillary beta/gamma zone width) in non-glaucomatous eyes was not significantly (P = 0.60) related with axial length in emmetropic or axially myopic eyes (axial length ≥23.5 mm), while it increased significantly (P<0.001; r: 0.32) with longer axial length in eyes with an axial length of <23.5mm. Ratio of mean DFD to disc diameter was 2.65 ± 0.30. If the ratio of disc-fovea distance to disc diameter was considered constant and if the individual disc diameter was calculated as the individual disc-fovea distance divided by the constant factor of 2.65, the resulting calculated disc diameter differed from the directly measured disc diameter by 0.16 ±0.13 mm (median: 0.13 mm, range: 0.00–0.89 mm) or 8.9 ± 7.3% (median: 7.4%; range: 0.00–70%) of the measured disc diameter. Conclusions DFD (mean: 4.76mm) increases with longer axial length, larger parapapillary alpha zone and parapapillary beta/gamma zone, and larger disc area. The axial elongation associated increase in DFD was due to an enlargement of parapapillary beta/gamma zone while the Bruch’s membrane opening-fovea distance did not enlarge with longer axial length. This finding may be of interest for the process of emmetropization and myopization. Due to its variability, the disc-fovea distance has only limited clinical value as a relative size unit for structures at the posterior pole.

Optic Disc - Fovea Angle: The Beijing Eye Study 2011

Purpose To determine the optic disc-fovea angle (defined as angle between the horizontal and the line between the optic disc center and the fovea) and to assess its relationships with ocular and systemic parameters. Methods The population-based cross-sectional Beijing Eye Study 2011 included 3468 individuals. A detailed ophthalmic examination was carried out. Using fundus photographs, we measured the disc-fovea angle. Results Readable fundus photographs were available for 6043 eyes of 3052 (88.0%) individuals with a mean age of 63.6±9.3 years (range: 50–91 years) and a mean axial length of 23.2±1.0 mm (range: 18.96–28.87 mm). Mean disc-fovea angle was 7.76 ± 3.63° (median: 7.65°; range: -6.3° to 28.9°). The mean inter-eye difference was 4.01 ± 2.94° (median: 3.49°; range: 0.00–22.3°). In multivariate analysis, larger disc-fovea angle was associated (regression coefficient r2: 0.08) with older age (P = 0.009; standardized regression coefficient beta: 0.05), thinner RNFL in the nasal superior sector (P<0.001; beta: -0.17), superior sector (P<0.001; beta: -0.10) and temporal superior sector (P<0.001; beta: -0.11) and thicker RNFL in the inferior sector (P<001; beta: 0.13), nasal inferior sector (P<001; beta: 0.13) and nasal sector (P = 0.007; beta: 0.06), higher prevalence of retinal vein occlusion (P = 0.02; beta: 0.04), and with larger cylindrical refractive error (P = 0.04; beta: 0.04). Conclusions The optic disc-fovea angle markedly influences the regional distribution of the RNFL thickness pattern. The disc-fovea angle may routinely be taken into account in the morphological glaucoma diagnosis and in the assessment of structure-function relationship in optic nerve diseases. Future studies may address potential associations between a larger disc-fovea angle and retinal vein occlusions and between the disc-fovea angle and the neuroretinal rim shape.

Lamina cribrosa thickness correlated with peripapillary sclera thickness

anaesthetic, the lower lid is gently retracted to produce an enlarged fornix and 2–3 drops of saline or artificial tears are instilled. The subject is then asked to look down slowly and suddenly the inferior angle will come into view (Fig. 1). By altering the position of the retracting finger up and down, the curvature of the surface of the puddle of fluid changes and the angle of view of the angle will alter. The magnification will also change a little. Saline drops give the clearer view but a viscous artificial tear is easier to manipulate especially when learning the technique. The limitation is that only the inferior angle can be viewed. However, this would be a useful technique when a contact gonioscope is inadvisable eg looking for a foreign body which might have fallen into the angle in the presence of a perforating injury, checking the position of the feet of an anterior chamber lens soon after surgery and in children. It would also be useful to optometrists who do not wish to use a contact gonioscope but wish to dilate the pupil for fundoscopy. Van Herick et al. (1969) method is often used by optometrist to gauge whether it is safe to dilate the pupil. Liquid gonioscopy, showing that the inferior angle is open, would provide further reassurance to the inexperienced optometrist. Furthermore liquid gonioscopy is cheap and readily available. The mean refractive index of the corneal epithelium, stromal anterior and posterior surfaces are 1.401 (SD ± 0.005), 1.380 (SD ± 0.005), and 1.373 (SD ± 0.001) respectively (Patel et al. 1995). For 0.9% NaCl the mean refractive index is1.33419 and for human tears average values were found to be 1.33698 ± 0.00110 (Craig et al. 1995). As there is little difference in refractive index, light from the angle passing from aqueous, through the cornea and into the tear film is only a little refracted and is shown as a straight line in Fig. 2. However as the critical angle for water ⁄ air is 49 , this ray (dotted line) is then totally internally reflected into the eye and the angle cannot be directly visualised. The addition of a pool of saline or artificial tears, changes the light path as shown (solid line) and the angle can be thus readily visualised.