Frank D. Verbraak

Recent developments in optical coherence tomography for imaging the retina

Optical coherence tomography (OCT) was introduced in ophthalmology a decade ago. Within a few years in vivo imaging of the healthy retina and optic nerve head and of retinal diseases was a fact. In particular the ease with which these images can be acquired considerably changed the diagnostic strategy used by ophthalmologists. The OCT technique currently available in clinical practice is referred to as time-domain OCT, because the depth information of the retina is acquired as a sequence of samples, over time. This can be done either in longitudinal cross-sections perpendicular to, or in the coronal plane parallel to the retinal surface. Only recently, major advances have been made as to image resolution with the introduction of ultrahigh resolution OCT and in imaging speed, signal-to-noise ratio and sensitivity with the introduction of spectral-domain OCT. Functional OCT is the next frontier in OCT imaging. For example, polarization-sensitive OCT uses the birefringent characteristics of the retinal nerve fibre layer to better assess its thickness. Blood flow information from retinal vessels as well as the oxygenation state of retinal tissue can be extracted from the OCT signal. Very promising are the developments in contrast-enhanced molecular optical imaging, for example with the use of scattering tuneable nanoparticles targeted at specific tissue or cell structures. This review will provide an overview of these most recent developments in the field of OCT imaging focussing on applications for the retina.

Selective Loss of Inner Retinal Layer Thickness in Type 1 Diabetic Patients with Minimal Diabetic Retinopathy

PURPOSE To determine whether type 1 diabetes preferentially affects the inner retinal layers by comparing the thickness of six retinal layers in type 1 diabetic patients who have no or minimal diabetic retinopathy (DR) with those of age- and sex-matched healthy controls. METHODS Fifty-seven patients with type 1 diabetes with no (n = 32) or minimal (n = 25) DR underwent full ophthalmic examination, stereoscopic fundus photography, and optical coherence tomography (OCT). After automated segmentation of intraretinal layers of the OCT images, mean thickness was calculated for six layers of the retina in the fovea, the pericentral area, and the peripheral area of the central macula and were compared with those of an age- and sex-matched control group. RESULTS In patients with minimal DR, the mean ganglion cell/inner plexiform layer was 2.7 microm thinner (95% confidence interval [CI], 2.1-4.3 microm) and the mean inner nuclear layer was 1.1 microm thinner (95% CI, 0.1-2.1 microm) in the pericentral area of the central macula compared to those of age-matched controls. In the peripheral area, the mean ganglion cell/inner plexiform layer remained significantly thinner. No other layers showed a significant difference. CONCLUSIONS Thinning of the total retina in type 1 diabetic patients with minimal retinopathy compared with healthy controls is attributed to a selective thinning of inner retinal layers and supports the concept that early DR includes a neurodegenerative component.

Decreased Retinal Ganglion Cell Layer Thickness in Patients with Type 1 Diabetes

PURPOSE. To determine which retinal layers are most affected by diabetes and contribute to thinning of the inner retina and to investigate the relationship between retinal layer thickness (LT) and diabetes duration, diabetic retinopathy (DR) status, age, glycosylated hemoglobin (HbA1c), and the sex of the individual, in patients with type 1 diabetes who have no or minimal DR. METHODS. Mean LT was calculated for the individual retinal layers after automated segmentation of spectral domain-optical coherence tomography scans of patients with diabetes and compared with that in control subjects. Multiple linear regression analysis was used to determine the relationship between LT and HbA1c, age, sex, diabetes duration, and DR status. RESULTS. In patients with minimal DR, the mean ganglion cell layer (GCL) in the pericentral area was 5.1 mum thinner (95% confidence interval [CI], 1.1-9.1 mum), and in the peripheral macula, the mean retinal nerve fiber layer (RNFL) was 3.7 mum thinner (95% CI, 1.3-6.1 mum) than in the control subjects. There was a significant linear correlation (R = 0.53, P < 0.01) between GCL thickness and diabetes duration in the pooled group of patients. Multiple linear regression analysis (R = 0.62, P < 0.01) showed that DR status was the most important explanatory variable. CONCLUSIONS. This study demonstrates GCL thinning in the pericentral area and corresponding loss of RNFL thickness in the peripheral macula in patients with type 1 diabetes and no or minimal DR compared with control subjects. These results support the concept that diabetes has an early neurodegenerative effect on the retina, which occurs even though the vascular component of DR is minimal.

Early Neurodegeneration in the Retina of Type 2 Diabetic Patients

PURPOSE The purpose of this study was to determine whether diabetes type 2 causes thinning of retinal layers as a sign of neurodegeneration and to investigate the possible relationship between this thinning and duration of diabetes mellitus, diabetic retinopathy (DR) status, age, sex, and glycemic control (HbA1c). METHODS Mean layer thickness was calculated for retinal layers following automated segmentation of spectral domain optical coherence tomography images of diabetic patients with no or minimal DR and compared with controls. To determine the relationship between layer thickness and diabetes duration, DR status, age, sex, and HbA1c, a multiple linear regression analysis was used. RESULTS In the pericentral area of the macula, the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and inner plexiform layer (IPL) were thinner in patients with minimal DR compared to controls (respective difference 1.9 μm, 95% confidence interval [CI] 0.3-3.5 μm; 5.2 μm, 95% CI 1.0-9.3 μm; 4.5 μm, 95% CI 2.2-6.7 μm). In the peripheral area of the macula, the RNFL and IPL were thinner in patients with minimal DR compared to controls (respective difference 3.2 μm, 95% CI 0.1-6.4 μm; 3.3 μm, 95% CI 1.2-5.4 μm). Multiple linear regression analysis showed DR status to be the only significant explanatory variable (R = 0.31, P = 0.03) for this retinal thinning. CONCLUSIONS This study demonstrated thinner inner retinal layers in the macula of type 2 diabetic patients with minimal DR than in controls. These results support the concept that early DR includes a neurodegenerative component.

A prospective, randomized trial of pyrimethamine and azithromycin vs pyrimethamine and sulfadiazine for the treatment of ocular toxoplasmosis.

OBJECTIVE To compare the effects of two treatment regimens, one of which included azithromycin, for the treatment of sight-threatening (near optic disk or fovea) ocular toxoplasmosis. DESIGN Prospective, randomized open-labeled multicenter study, masked in part with regard to evaluation. METHODS PARTICIPANTS TOTAL ENROLLMENT: 46 patients with sight-threatening ocular toxoplasmosis; pyrimethamine and azithromycin group: 24 patients; pyrimethamine and sulfadiazine group: 22 patients. INTERVENTION Patients were randomized into two treatment regimens. Group 1 was treated with pyrimethamine and azithromycin complemented with folinic acid and the addition of prednisone from day 3. Group 2 was treated with pyrimethamine and sulfadiazine complemented with folinic acid and the addition of prednisone from day 3. Patients used study medications daily for 4 weeks. Ocular and laboratory examinations were performed at least weekly during the observation period. The study was masked in part with regard to evaluation. MAIN OUTCOME MEASURES An assessment was made of the time to resolution of the intraocular inflammatory activity, the size of the retinochoroidal lesion, and visual acuity before and after the treatment as well as all adverse effects of treatments. RESULTS Adverse effects were more frequent in the pyrimethamine/sulfadiazine group (P <.04), and three patients in this group had to discontinue treatment. The time to resolution of inflammatory activity, decrease in size of retinochoroidal lesions, and optimal visual acuity did not differ between the two treatment groups. The number of patients who developed recurrences during the first year after treatment was similar for both groups. CONCLUSIONS The efficacy of the multidrug regimen with pyrimethamine and azithromycin was similar to the standard treatment with pyrimethamine and sulfadiazine. However, the frequency and severity of adverse effects was significantly lower with a regimen containing pyrimethamine and azithromycin. Multidrug therapy with the combination of pyrimethamine and azithromycin appears to be an acceptable alternative for treatment of sight-threatening ocular toxoplasmosis.

Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus

Significance Diabetic retinopathy (DR), a primary cause of blindness, is characterized by microvascular abnormalities. Recent evidence suggests that retinal diabetic neuropathy (RDN) also occurs in people with diabetes, but little is known about the temporal relationship between DR and RDN. This longitudinal study in people with diabetes with no or minimal DR shows that RDN precedes signs of microvasculopathy and that RDN is progressive and independent of glycated hemoglobin, age, and sex. This finding was further confirmed in human donor eyes and in two experimental mouse models of diabetes. The results suggest that RDN is not ischemic in origin and represent a shift in our understanding of the pathophysiology of this complication of diabetes that potentially affects vision in all people with diabetes mellitus. Diabetic retinopathy (DR) has long been recognized as a microvasculopathy, but retinal diabetic neuropathy (RDN), characterized by inner retinal neurodegeneration, also occurs in people with diabetes mellitus (DM). We report that in 45 people with DM and no to minimal DR there was significant, progressive loss of the nerve fiber layer (NFL) (0.25 μm/y) and the ganglion cell (GC)/inner plexiform layer (0.29 μm/y) on optical coherence tomography analysis (OCT) over a 4-y period, independent of glycated hemoglobin, age, and sex. The NFL was significantly thinner (17.3 μm) in the eyes of six donors with DM than in the eyes of six similarly aged control donors (30.4 μm), although retinal capillary density did not differ in the two groups. We confirmed significant, progressive inner retinal thinning in streptozotocin-induced “type 1” and B6.BKS(D)-Leprdb/J “type 2” diabetic mouse models on OCT; immunohistochemistry in type 1 mice showed GC loss but no difference in pericyte density or acellular capillaries. The results suggest that RDN may precede the established clinical and morphometric vascular changes caused by DM and represent a paradigm shift in our understanding of ocular diabetic complications.

Evaluation of central serous retinopathy with en face optical coherence tomography

Background: The diagnosis of idiopathic central serous retinopathy (CSR) is usually based on biomicroscopy and fluorescein angiography (FA). The optical coherence tomography (OCT) ophthalmoscope produces en face OCT scans (OCT C-scans) and provides additional information not readily available by conventional imaging techniques. The authors describe the characteristic features observed in patients with a clinical diagnosis of CSR using the OCT ophthalmoscope. Methods: 38 eyes with a clinical diagnosis of CSR, seen at the Academic Medical Centre (Amsterdam, Netherlands) and the New York Eye and Ear Infirmary (New York, USA) between August 2002 and March 2004, were evaluated with standard digital FA and scanned with the OCT ophthalmoscope. Results: Nine of 38 eyes had no serous neurosensory detachment (inactive CSR) when scanned with the OCT ophthalmoscope. Characteristics for active CSR (n = 29) were large neurosensory detachment (23/29), subretinal hyper-reflective deposits (20/29), and pigment epithelial detachment (15/29). One third of the patients, either active or inactive, had multiple small pigment epithelial detachments located both within and outside the neurosensory detachment. Conclusion: The OCT ophthalmoscope provides complementary morphological information on patients with CSR. The presence of more diffuse retinal pigment epithelium (RPE) changes lends further support to the concept that CSR is a diffuse rather than localised RPE anomaly.

Decreased optical coherence tomography‐measured pericentral retinal thickness in patients with diabetes mellitus type 1 with minimal diabetic retinopathy

Aim: A comparison of retinal thickness (RT) measurements with optical coherence tomography (OCT) in patients with type 1 diabetes mellitus (DM) and no or minimal diabetic retinopathy (DR) versus healthy controls. Methods: Fifty-three patients with type 1 DM with no or minimal DR underwent full ophthalmic examination, fundus photography and OCT. Mean RT measured by OCT was calculated for the central fovea, the fovea, the pericentral and the peripheral area of the macula, and compared to healthy controls. Results: Mean RT in the pericentral area was lower in patients with minimal DR (267 µm ± 20 µm; n = 23) compared to healthy controls (281 µm ±13 µm; p = 0.005; n = 28). Mean pericentral RT in patients without DR (276 µm ±14 µm; n = 30) was less than pericentral RT in healthy controls, but higher than in patients with minimal DR, without being statistically significant. None of the other regions showed a significant change. Conclusion: In this study a significantly decreased pericentral RT was measured in patients with minimal DR compared to healthy controls. This could be explained by a loss of intraretinal neural tissue in the earliest stage of DR.

Effect of age on individual retinal layer thickness in normal eyes as measured with spectral-domain optical coherence tomography.

PURPOSE To determine the effect of age on the thickness of individual retinal layers, measured with spectral-domain optical coherence tomography (SD-OCT), in a population of healthy Caucasians. METHODS One hundred and twenty subjects with an age ranging between 18 and 81 years were examined with SD-OCT. Mean layer thickness was calculated for seven retinal layers, in the fovea (region 1 of the 9 Early Treatment Diabetic Retinopathy Study [ETDRS] regions); in the pericentral ring (ETDRS regions 2 to 5); and the peripheral ring (ETDRS regions 6 to 9) following automated segmentation using the Iowa Reference Algorithm. In addition, mean peripapillary retinal nerve fiber layer (RNFL) thickness was measured. The partial correlation test was performed on each layer to determine the effect of age on layer thickness, while correcting for spherical equivalent, sex, and Topcon image quality factor as confounders, followed by Bonferroni corrections to adjust for multiple testing. RESULTS The thickness of the peripapillary RNFL (R = -0.332; P < 0.001); pericentral ganglion cell layer (R = -0.354, P < 0.001); peripheral inner plexiform layer (R = -0.328, P < 0.001); and foveal outer segment layer (R = -0.381, P < 0.001) decreased significantly with increasing age. Foveal RPE thickness (R = 0.467, P < 0.001) increased significantly with increasing age; other layers showed no significant differences with age. CONCLUSIONS Several macular layers and the peripapillary RNFL thickness showed significant changes correlated with age. This should be taken into consideration when analyzing macular layers and the peripapillary RNFL in SD-OCT studies of retinal diseases and glaucoma.

Association of visual function and ganglion cell layer thickness in patients with diabetes mellitus type 1 and no or minimal diabetic retinopathy

Diabetic retinopathy (DR) classically presents with micro-aneurysms, small haemorrhages and/or lipoprotein exudates. Several studies have indicated that neural loss occurs in DR even before vascular damage can be observed. This study evaluated the possible relationship between structure (spectral domain-optical coherence tomography) and function (Rarebit visual field test) in patients with type 1 diabetes mellitus and no or minimal diabetic retinopathy (DR). Results demonstrated loss of macular visual function and corresponding thinning of the ganglion cell layer (GCL) in the pericentral area of the macula of diabetic patients (Rs = 0.65, p < 0.001). In multivariable logistic regression analysis, GCL thickness remained an independent predictor of decreased visual function (OR 1.5, 95% CI 1.1-2.1). Early DR seems to include a neurodegenerative component.