Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in 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)-Lepr(db)/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.

Development of retinal structure in perinatally HIV-infected children and adolescents: A longitudinal and cross-sectional assessment.

In perinatally HIV-infected (PHIV) children, cross-sectional studies reported on subtle structural retinal differences and found associations between the retina and structural brain changes. Our objective is to investigate whether neuroretinal development in PHIV children is similar to the development in healthy matched controls and to explore associations with the brain structure. We measured RT using optical coherence tomography (OCT) on two occasions in 21 PHIV children or adolescents and 23 matched controls-all with good visual acuity-with a mean interval of 4.6 years (SD 0.3). We also included 22 participants (11 PHIV children and 11 controls) together with the follow-up group for a cross-sectional assessment using a different OCT device. Magnetic resonance imaging (MRI) was used to assess the white matter microstructure. We used linear (mixed) models to assess changes in RT and its determinants (over time), adjusting for age and sex. The development of the retina was similar between the PHIV adolescents and controls. In our cohort, we found that changes in the peripapillary RNFL was significantly associated with changes in WM microstructural makers: fractional anisotropy (coefficient = 0.030, p = 0.022) and radial diffusivity (coefficient = -0.568, p = 0.025). We found comparable RT between groups. A thinner pRNFL was associated with lower WM volume (coefficient = 0.117, p = 0.030). PHIV children or adolescents appear to have a similar development of the retinal structure. In our cohort, the associations between RT and MRI biomarkers underscore the relation between retina and brain.

Implantation of the Black Artisan Iris-Claw Intraocular Lens: A Case Series.

In this case series, we report the use of the black Artisan iris-claw intraocular lens (IOL) (Ophtec, The Netherlands) in 6 patients with various visually debilitating symptoms requesting occlusion of one eye. Between 2016 and 2019, 6 (5 female, 1 male) patients underwent implantation of the custom-made black Artisan iris-claw IOL after other management strategies had failed to relieve their symptoms. The black Artisan IOL is an opaque anterior chamber IOL that is fixated to the iris by enclavation. Data were obtained from the electronic patient records (Epic, Verona, WI, USA). All implantation surgeries were uneventful. In terms of outcomes, 4 patients (67%) were satisfied with the result. In 2 patients (33%), the dysphotopic symptoms were not resolved, and these patients opted for either an enucleation or an evisceration. In conclusion, a black Artisan IOL is a valuable and - if needed - reversible option in the management of patients suffering from monocular debilitating visual symptoms leading to disturbances of binocular vision. The clinical presentation leading to the implantation of a pupil-occluding IOL varies and patient satisfaction following implantation is variable. Careful preoperative evaluation of patient factors and expectations, and stepped-care management is recommended to minimize treatment failure. Pupil-occluding lens implantation is often the last step in the treatment of intractable visual complaints in eyes with complex ophthalmologic history, before evisceration or enucleation.

Inflammatory and Neuronal Biomarkers Associated With Retinal Thinning in Pediatric HIV.

Purpose: The pathophysiology of neuroretinal thinning in children with human immunodeficiency virus (HIV) is poorly understood. The current study aimed to assess whether neuroretinal thinning in clinically stable perinatally HIV-infected children was associated with biomarkers of immune activation, inflammation, and neuronal damage. Methods: Inflammation-associated and neuronal damage markers were measured in blood and cerebrospinal fluid (CSF) of HIV-infected children aged 8 to 18 years. Using mixed-effects regression analyses, we assessed associations between these biomarkers and neuroretinal layer thickness, as measured with spectral-domain optical coherence tomography. Results: Thirty-two HIV-infected children (median age 13.6 years, 50% male) were included. Blood plasma levels of interleukin-6, monocyte chemoattractant protein-1, and soluble intercellular adhesion molecule-1 were inversely correlated with foveal inner plexiform layer thickness (coef = -4.40, P < 0.001; coef = -9.67, P = 0.047; coef = -10.48, P = 0.042, respectively). Plasma interleukin-6 was inversely correlated with foveal ganglion cell layer thickness (coef = -2.49, P = 0.010). Total Tau levels in CSF were inversely correlated with outer nuclear layer and inner segments thickness (foveal: coef = -19.3, P = 0.029; pericentral: coef = -18.09, P = 0.006) and pericentral total retinal thickness (coef = -28.2, P = 0.017). Conclusions: Neuroretinal thinning was associated with inflammation-associated and neuronal injury biomarkers in a cohort of antiretroviral therapy-treated perinatally HIV-infected children. These findings suggest that ongoing immune activation, inflammation, and neuronal injury occur in parallel with retinal thinning in pediatric HIV.

HIV-Associated Neuroretinal Disorder in Patients With Well-Suppressed HIV-Infection: A Comparative Cohort Study.

PURPOSE: Loss of neuroretinal structure and function, ascribed to a 'HIV-associated Neuroretinal Disorder' (HIV-NRD), in the absence of ocular opportunistic infections, has been reported in HIV-infected individuals treated with combination antiretroviral therapy (cART). Whether HIV-infected individuals with prolonged well-suppressed infection remain at risk for HIV-NRD, is unknown. METHODS: Ninety-two HIV-infected men with suppressed viremia on cART for at least 12 months (HIV+) and 63 HIV-uninfected, highly comparable, male controls (HIV-), aged at least 45 years, underwent functional measurements of spatial (Pelli Robson contrast sensitivity [PR CS]) and temporal contrast sensitivity (TCS) and straylight, as well as spectral-domain optical coherence tomography analysis measured total and individual retinal layer thickness. Mixed-linear regression models were used to assess possible associations between HIV-related and ocular parameters, while accounting for several confounders. RESULTS: Pelli Robson CS was significantly lower in HIV+ (1.89 vs. 1.93 logCS, P value = 0.001), while TCS values did not differ (2.17 vs. 2.17 logCS; P value = 0.888). Straylight values were higher in HIV+ (1.15 vs. 1.09 log units; P value = 0.026). Peripheral total retinal thickness in the HIV+ group was increased compared with HIV- (+4.6 µm, P value = 0.029), predominantly due to an increase in inner nuclear layer (+1.04 µm, P value = 0.006) and outer plexiform layer (+0.95 µm, P value = 0.006) thickness. CONCLUSIONS: Pelli Robson CS was significantly reduced in HIV-infected individuals, although the loss was one letter and likely not clinically relevant. Instead of an expected neuroretinal thinning, an increase of retinal thickness was detected in the HIV-infected group. These findings should be confirmed and further explored in longitudinal studies. Clinical Trial registered at www.clinicaltrials.gov (identifier: NCT01466582).

The Eye as a Window to the Brain: Neuroretinal Thickness Is Associated With Microstructural White Matter Injury in HIV-Infected Children.

PURPOSE: Despite combination antiretroviral therapy (cART), perinatal HIV-infection can cause decreased gray and white matter volume, microstructural white matter injury, and retinal structural abnormalities. As neuroretinal tissue is directly connected to the brain, these deficits may have a shared pathogenesis. We aimed to assess associations between neuroretinal thickness and cerebral injury in cART-treated perinatally HIV-infected children and healthy controls. METHODS: This cross-sectional observational study included 29 cART-treated perinatally HIV-infected children and 35 matched healthy controls. All participants underwent 3.0 Tesla magnetic resonance imaging (MRI), determining gray and white matter volumes from T1-weighted sequences, and white matter diffusivity using diffusion tensor imaging (DTI). Regional individual and total neuroretinal layer thickness was quantified using spectral-domain optical coherence tomography. We explored associations between retinal and cerebral parameters using multivariable linear regression analysis. RESULTS: In HIV-infected children, lower foveal and pericentral neuroretinal thickness was associated with damaged white matter microstructure, in terms of lower fractional anisotropy and higher mean and radial diffusivity. In healthy controls only, neuroretinal thickness was associated with gray and white matter volume. CONCLUSIONS: Decreased neuroretinal thickness is associated with microstructural white matter injury, but not with lower cerebral volume in HIV-infected children. This suggests that HIV-induced retinal thinning and microstructural white matter injury may share a common pathogenesis, and longitudinal assessment of neuroretinal alterations in parallel with MRI and neuroinflammatory markers may further our insight into the pathogenesis of HIV-induced cerebral injury in children.

Neuroretinal Degeneration in HIV Patients Without Opportunistic Ocular Infections in the cART Era.

Subtle structural and functional retinal abnormalities, termed 'HIV-associated Neuroretinal Disorder (HIV-NRD)', have been reported in HIV patients receiving combination antiretroviral therapy (cART), without infectious retinitis or any apparent fundus abnormalities otherwise. In this review, we provide an overview of studies investigating HIV-NRD in HIV patients without opportunistic ocular infections in the cART era, and try to elucidate underlying mechanisms and associated risk factors. Most studies focused on patients with severe immune-deficiency and demonstrated that patients with nadir CD4 counts<100 cells/µL are most at risk for neuroretinal damage, with a thinner retinal nerve fiber layer, subtle loss of color vision and/or contrast sensitivity, visual field deficits, and subnormal electrophysiological responses. In contrast, alterations in retinal vascular calibers and retinal blood flow were not associated with nadir CD4 counts, but instead with detectable viremia, suggesting a role for (chronic) inflammation in microvascular damage. Although the alterations in visual function are subtle, they can lead to difficulties in activities, such as reading or driving, thereby affecting quality of life. Since HIV has become a chronic disease, its long-term effects with respect to visual function loss become more important, as is recently emphasized by a longitudinal study, reporting that AIDS patients with HIV-NRD have higher risks of developing bilateral visual impairment and even blindness than patients without HIV-NRD. The question remains whether patients with high (>350 cells/µL) nadir CD4 counts and well-suppressed HIV infection on cART remain at risk for HIV-NRD, as this group constitutes a growing part of the aging HIV-infected population.

Retinal Structure and Function in Perinatally HIV-Infected and cART-Treated Children: A Matched Case-Control Study.

PURPOSE: Subtle structural and functional neuroretinal changes have been described in human immunodeficiency virus (HIV)-infected adults without retinitis treated with combination antiretroviral therapy (cART). However, studies on this subject in HIV-infected children are scarce. This study aimed to assess the presence of (neuro)retinal functional and structural differences between a group of perinatally HIV-infected children on cART and age-, sex-, ethnicity-, and socioeconomically matched healthy controls. METHODS: All participants underwent an extensive ophthalmological examination, including functional tests as well as optical coherence tomography, to measure individual retinal layer thicknesses. Multivariable mixed linear regression models were used to assess possible associations between HIV status (and other HIV-related parameters) and ocular parameters, while accounting for the inclusion of both eyes and several known confounders. RESULTS: Thirty-three HIV-infected children (median age 13.7 years [interquartile range (IQR), 12.2-15.8], median CD4+ T-cell count 760 cells/mm3, 82% with an undetectable HIV viral load [VL]), and 36 controls (median age 12.1 years [IQR, 11.5-15.8]) were included. Contrast sensitivity (CS) was significantly lower in the HIV-infected group (1.74 vs. 1.76 logCS; P = 0.006). The patients had a significantly thinner foveal thickness (-11.2 µm, P = 0.012), which was associated with a higher peak HIV VL (-10.3 µm per log copy/mL, P = 0.016). CONCLUSIONS: In this study, we found a decrease in foveal thickness in HIV-infected children, which was associated with a higher peak VL. Longitudinal studies are warranted to confirm our findings and to determine the course and clinical consequences of these foveal changes.

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.