Dysregulated 24 h melatonin secretion associated with intrinsically photosensitive retinal ganglion cell function in diabetic retinopathy: a cross-sectional study.

AIMS/HYPOTHESIS: The aim of this study was to explore whether diabetic retinopathy is associated with alterations of the circadian system, and to examine the role of reduced intrinsically photosensitive retinal ganglion cell (ipRGC) function. METHODS: Participants with type 2 diabetes, with diabetic retinopathy (n=14) and without diabetic retinopathy (n=9) underwent 24 h blood sampling for melatonin and cortisol under controlled laboratory conditions. ipRGC function was inferred from the post-illumination pupil response (PIPR). Habitual sleep duration, efficiency and variability were assessed by actigraphy. RESULTS: Participants with diabetic retinopathy compared to participants without diabetic retinopathy had smaller PIPR (p=0.007), lower 24 h serum melatonin output (p=0.042) and greater day-to-day sleep variability (p=0.012). By contrast, 24 h cortisol profiles, sleep duration and efficiency were similar in both groups. Six individuals with diabetic retinopathy had no detectable dim-light melatonin onset. PIPR correlated with 24 h mean melatonin levels (r=0.555, p=0.007). CONCLUSIONS/INTERPRETATION: ipRCG dysfunction in diabetic retinopathy is associated with disruptions of the 24 h melatonin rhythm, suggesting circadian dysregulation in diabetic retinopathy.

Greater sleep variability is associated with higher systemic inflammation in type 2 diabetes.

Sleep irregularity and variability have been shown to be detrimental to cardiometabolic health. The present pilot study explored if higher day-to-day sleep irregularity and variability were associated with systemic inflammation, as assessed by high-sensitivity C-reactive protein, in type 2 diabetes. Thirty-five patients with type 2 diabetes (mean age 54.3 years, 54.3% female) who were not shift-workers participated. The presence of diabetic retinopathy was determined. The standard deviation of sleep duration and sleep midpoint across all recorded nights were used to quantify sleep variability and regularity, respectively, assessed by 14-day actigraphy. The presence and severity of sleep apnea were assessed using an overnight home monitor. Low-density lipoprotein, haemoglobin A1C and high-sensitivity C-reactive protein were collected. Multiple regression analysis using natural-log-transformed values was performed to establish an independent association between sleep variability and high-sensitivity C-reactive protein. Twenty-two (62.9%) patients had diabetic retinopathy. The median (interquartile range) of high-sensitivity C-reactive protein was 2.4 (1.4, 4.6) mg L-1 . Higher sleep variability was significantly associated with higher high-sensitivity C-reactive protein (r = 0.342, p = 0.044), as was haemoglobin A1C (r = 0.431, p = 0.010) and low-density lipoprotein (r = 0.379, p = 0.025), but not sleep regularity, sleep apnea severity or diabetic retinopathy. Multiple regression analysis showed that higher sleep variability (B = 0.907, p = 0.038) and higher HbA1c (B = 1.519, p = 0.035), but not low-density lipoprotein, contributed to higher high-sensitivity C-reactive protein. In conclusion, higher sleep variability in patients with type 2 diabetes who were not shift-workers was independently associated with higher systemic inflammation, conferring increased cardiovascular risk. Whether sleep interventions to reduce sleep variability can reduce systemic inflammation and improve cardiometabolic health should be investigated.

POSTERIOR TRACTIONAL MEMBRANES FOLLOWING ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR FOR RETINOPATHY OF PREMATURITY.

PURPOSE: To report two cases of tractional membrane formation following treatment with anti-vascular endothelial growth factor therapy in infants with Stage-3 retinopathy of prematurity. METHODS: Retrospective review of electronic medical record for historical information, clinical examination documentation, and imaging from fundus photography, retinal ultrasonography, and fluorescein angiography. RESULTS: Two patients with Stage-3 retinopathy of prematurity, previously treated with laser therapy and intravitreal bevacizumab, were referred to our institution for tractional membranes. The first case is of a male infant with Zone-II disease that progressed to Stage 4A with evidence of inferotemporal tractional retinal detachment only in the left eye. The second case is of a male infant with stable Zone-I disease with an epiretinal membrane in the left eye.Pars plicata vitrectomy and membranectomy were required for both cases because of the concern for subsequent tractional retinal detachment. CONCLUSION: Formation of tractional retinal membranes has been associated with anti-vascular endothelial growth factor therapy. These cases describe the formation of posterior tractional membranes after anti-vascular endothelial growth factor therapy. This potential ocular outcome should be considered when determining treatment plans for retinopathy of prematurity.

Relationship between Intrinsically Photosensitive Ganglion Cell Function and Circadian Regulation in Diabetic Retinopathy.

BACKGROUND: Intrinsically photosensitive retinal ganglion cells (ipRGCs) control non-visual light responses (e.g. pupillary light reflex and circadian entrainment). Patients with diabetic retinopathy (DR) show reduced ipRGC function, as inferred by abnormalities in the post illumination pupil response (PIPR). We explored whether ipRGC function in DR is associated with circadian outputs and sleep/wake behavior. METHODS: Forty-five participants (15 without diabetes, 15 with type 2 diabetes (T2D) and no DR, 15 with T2D and DR) participated. ipRGC function was inferred from the PIPR (pupil size following stimulus offset). Circadian outputs were melatonin amplitude (overnight urinary 6-sulfatoxymelatonin (aMT6s)) and timing (dim light melatonin onset (DLMO)), and evening salivary cortisol levels. Sleep/wake patterns were measured with wrist actigraphy and insomnia symptoms were assessed subjectively. RESULTS: Patients with T2D and DR had smaller PIPR and lower urinary aMT6s than other groups (p < 0.001). In adjusted regression models, smaller PIPR was associated with lower urinary aMT6s (ß = 4.552, p = 0.005). Patients with DR were more likely to have no detectable DLMO (p = 0.049), higher evening salivary cortisol, greater insomnia symptoms and greater sleep variability compared to other groups. Sleep duration, efficiency and rest-activity rhythms were similar. CONCLUSION: Reduced ipRGC function in DR is associated with circadian dysregulation and sleep disturbances, although a causal relationship cannot be established in this cross-sectional study. Prospective mechanistic and intervention studies examining circadian and sleep health in these patients are warranted.

Contrast sensitivity is associated with outer-retina thickness in early-stage diabetic retinopathy.

PURPOSE: To determine the relationship between contrast sensitivity (CS) and outer-retina thickness (ORT) in diabetics who have minimal or no diabetic retinopathy (DR). METHODS: Twenty non-diabetic control subjects and 40 type-2 diabetic subjects participated (20 had no clinically apparent DR [NDR] and 20 had mild non-proliferative DR [NPDR]). No subject had a history of treatment for macular oedema. Letter CS, microperimetry (MP) sensitivity and visual acuity (VA) were measured. Letter CS and MP measurements were performed over the central 6° of the visual field. Spectral domain optical coherence tomography (SD-OCT) images were obtained at corresponding locations, outer-retina thickness was quantified, and structure-function relationships were evaluated. RESULTS: Analysis of variance indicated significant letter CS differences among the groups (p < 0.001). Letter CS was reduced significantly for the mild NPDR group (p < 0.001; 33% reduction), but not the NDR group (p = 0.08). There were no significant differences in MP sensitivity or ORT among the groups (both p > 0.10). Nevertheless, Hoeffding's D tests indicated significant associations between ORT and letter CS (p < 0.001) and between ORT and MP sensitivity for the mild NPDR group (p = 0.01). VA was not significantly associated with ORT for either diabetic group (both p > 0.49). CONCLUSIONS: Outer-retina thickness is associated with letter CS and MP sensitivity, but not VA, in mild NPDR. This finding highlights the usefulness of simple letter CS measures and suggests neural dysfunction can occur in the absence of marked structural abnormalities in early-stage DR.

Zone of retinal vascularization and refractive error in premature eyes with and without spontaneously regressed retinopathy of prematurity.

PURPOSE: To evaluate the relationship between zone of retinal vascularization and refractive error in premature infants without retinopathy of prematurity (ROP) or with spontaneously regressed ROP. METHODS: The medical records of neonates screened for ROP between 2009 and 2015 at a tertiary academic center were reviewed retrospectively. Cases included untreated eyes with spontaneously regressed ROP; premature eyes without a diagnosis of ROP were control subjects. Primary outcomes were zone of retinal vascularization and refractive error, determined by cycloplegic retinoscopy (CR). RESULTS: Of 378 eyes evaluated, 184 had ROP, 24 of which underwent treatment and were excluded. Mean corrected age at first CR was 7.5 months. Seventeen eyes without ROP were myopic at first CR (8.8%), compared to 35 eyes with regressed ROP (21.9%). No untreated eyes had halted vasculature in zone I; notably, 44% of spontaneously regressed zone II eyes were myopic. Irrespective of ROP status, CR significantly differed by zone of vascularization (P < 0.001), with more myopia occurring with posterior halting of vascularization. For all eyes, CR significantly differed between complete vascularization versus zone II (P < 0.0001) and zone III versus zone II (P = 0.001); zone III versus complete vascularization did not statistically differ (P = 0.15). This relationship held true for untreated, spontaneously regressed ROP eyes (P < 0.01, P = 0.01, P = 0.8343). CONCLUSIONS: More myopic refraction occurred in neonates screened for ROP with posterior halting of vascularization. Patients with halted vascular growth in zone II should be closely monitored for myopia and refractive amblyopia.

Electrophysiological and pupillometric measures of inner retina function in nonproliferative diabetic retinopathy.

PURPOSE: To evaluate three measures of inner retina function, the pattern electroretinogram (pERG), the photopic negative response (PhNR), and the post-illumination pupil response (PIPR) in diabetics with and without nonproliferative diabetic retinopathy (NPDR). METHODS: Fifteen non-diabetic control subjects and 45 type 2 diabetic subjects participated (15 have no clinically apparent retinopathy [NDR], 15 have mild NPDR, and 15 have moderate/severe NPDR). The pERG was elicited by a contrast-reversing checkerboard pattern, and the PhNR was measured in response to a full-field, long-wavelength flash presented against a short-wavelength adapting field. The PIPR was elicited by a full-field, 450 cd/m2, short-wavelength flash. All responses were recorded and analyzed using conventional techniques. One-way ANOVAs were performed to compare the pERG, PhNR, and PIPR among the control and diabetic groups. RESULTS: ANOVA indicated statistically significant differences among the control and diabetic subjects for all three measures. Holm-Sidak post hoc comparisons indicated small, nonsignificant reductions in the pERG (8%), PhNR (8%), and PIPR (10%) for the NDR group compared to the controls (all p > 0.25). In contrast, there were significant reductions in the pERG (35), PhNR (34%), and PIPR (30%) for the mild NPDR group compared to the controls (all p < 0.01). Likewise, there were significant reductions in the pERG (40%), PhNR (32%), and PIPR (32%) for the moderate/severe NPDR group compared to the controls (all p < 0.01). CONCLUSION: Abnormalities of the pERG, PhNR, and PIPR suggest inner retina neural dysfunction in diabetics who have clinically apparent vascular abnormalities. Taken together, these measures provide a noninvasive, objective approach to study neural dysfunction in these individuals.

AMPLITUDE LOSS OF THE HIGH-FREQUENCY FLICKER ELECTRORETINOGRAM IN EARLY DIABETIC RETINOPATHY.

PURPOSE: To evaluate retinal dysfunction in diabetic patients who have mild or no nonproliferative diabetic retinopathy (DR) using the high-frequency flicker electroretinogram. METHODS: Light-adapted flicker electroretinograms were recorded from 15 diabetic patients who have no clinically apparent retinopathy, 15 diabetic patients who have mild nonproliferative DR, and 15 nondiabetic, age-equivalent controls. Electroretinograms were elicited by full-field flicker at 2 temporal frequencies, 31.25 and 62.5 Hz, and were recorded using conventional techniques. Amplitude and timing of the flicker responses were compared among the groups and correlated with clinical characteristics including age, acuity, disease duration, and HbA1c. RESULTS: The 31.25-Hz flicker amplitude was slightly, but nonsignificantly, smaller for subjects with no DR and mild nonproliferative DR , compared with the control group (both t < 1.38, P > 0.31); small, nonsignificant response delays for both patient groups were also observed (both t < 1.57, P > 0.12). By contrast, there were significant amplitude reductions for the 62.5-Hz flicker stimulus: mean amplitude was reduced by 32% for subjects with no DR and by 41% for subjects with mild nonproliferative DR (both t > 2.92 and P < 0.01). Response timing at 62.5 Hz did not differ significantly from control for either group (both t < 1.2 and P > 0.39). Electroretinogram amplitude and timing were not correlated significantly with clinical characteristics. CONCLUSION: The 62.5-Hz flicker electroretinogram is useful for evaluating retinal dysfunction in diabetic patients who have mild or no DR because this response can be significantly reduced. Attenuation of the high-frequency flicker electroretinogram, which is primarily generated by bipolar cells, suggests a relatively early retinal site of neural dysfunction.

Surgical Management of an Externally Protruding, Perforating Intraocular Foreign Body.

Ru-ik Chee Felix Y. Chau In this case of a perforating eye injury by a 2-inch-long nail that went through the cornea, lens, and posterior eye wall, the authors describe a combined external, anterior, and posterior segment surgical approach that resulted in safe and successful removal of the foreign body. Initial external trimming of the protruding nail facilitated the use of a noncontact viewing system. Combined limbal and pars plana placement of the vitrectomy cannulas optimized access to both anterior and posterior intraocular structures. Most importantly, careful removal of potential sources of foreign body adhesion to intraocular structures prior to extraction likely increased the likelihood for a successful clinical outcome. Care was taken to remove as much of the vitreous as possible and to keep the eye formed. The patient recovered 20/25+2 vision with aphakic correction.

Recognition of Fungal Keratitis in Boston Type I Keratoprosthesis: Importance of Awareness and Novel Identification of Exophiala phaeomuriformis.

PURPOSE: To present a case of Exophiala phaeomuriformis fungal keratitis to demonstrate the heightened concern for fungal infection in patients with a keratoprosthesis and to highlight the rare involvement of Exophiala phaeomuriformis. METHODS: Case report. RESULTS: Exophiala phaeomuriformis was identified in a susceptible patient 7 years after Boston type I keratoprosthesis (KPro) implantation. CONCLUSIONS: Although fungal infiltration after KPro placement does not represent a novel clinical infection, identification of the rare Exophiala species in a patient with a KPro has not been reported and provides an opportunity for reflection on fungal identification, prophylaxis, and prevention in this vulnerable patient population.

Congenital cavitary optic disc anomaly and Axenfeld's anomaly in Wolf-Hirschhorn syndrome: A case report and review of the literature.

BACKGROUND: Wolf-Hirschhorn syndrome is a rare genetic syndrome caused by a heterozygous deletion on chromosome 4p16.3 and is characterized by a "Greek warrior helmet" facies, hypotonia, developmental delay, seizures, structural central nervous system defects, intrauterine growth restriction, sketelal anomalies, cardiac defects, abnormal tooth development, and hearing loss. A variety of ocular manifestations may occur in up to 40% of patients. MATERIALS/METHODS: We report the genetic testing results, systemic findings, and complete ophthalmologic examination findings in a patient with Wolf-Hirschhorn syndrome, including external photography, RetCam3 (Clarity Medical Systems, Pleasonton, CA) goniography, and fundus photography. In addition, we review the literature on ocular manifestations of Wolf-Hirschhorn syndrome. RESULTS: Microarray analysis revealed an unbalanced translocation between 4p16.3-15.3 and Xp22.33-p22.2. Systemic findings included "Greek warrior helmet" facies, hypotonia, cleft palate, neonatal tooth eruption, talipes equinovarus, bilateral clinodactyly, clitoromegaly, partial agenesis of the corpus callosum, bilateral renal hypoplasia, and two atrial septal defects. Ocular findings included normal intraocular pressures and corneal diameters, large-angle exotropia, downward slanting of the palpebral fissures, absent eyelid creases, upper and lower eyelid retraction with shortage of the anterior eyelid lamellae, euryblepharon, lagophthalmos with poor Bell's reflex and exposure keratopathy, hypertelorism, Axenfeld's anomaly, megalopapillae, and cavitary optic disc anomaly. CONCLUSIONS: We describe the ocular phenotype of a patient with Wolf-Hirschhorn syndrome, including the rare descriptions and photographs of Axenfeld's anomaly, megalopapilla, and cavitary optic disc anomaly in this condition.

Epidemiological trends in 1452 cases of retinoblastoma from the Surveillance, Epidemiology, and End Results (SEER) registry.

OBJECTIVE: To assess retinoblastoma epidemiological trends in the Surveillance, Epidemiology, and End Results (SEER) registry. METHODS: All cases of retinoblastoma in the SEER database from 1973 to 2009 were identified. Kaplan-Meier survival analyses were performed for pathological grade, patient age, sex, year of diagnosis, and treatment modality. Cox proportional hazards regression assessed the impact of patient and tumour characteristics on survival. RESULTS: 1452 cases of retinoblastoma were analyzed. The mean patient age at diagnosis was 1.44 years. The tumour was unilateral in 71.0% and bilateral in 29.0%. The mean follow-up was 129.1 months. Overall survival increased during the study interval. Patients with bilateral tumours were diagnosed at an earlier age (0.46 years) than patients with unilateral disease (1.77 years; p < 0.0001). Bilateral retinoblastoma (90.3% 10-year overall survival) was associated with decreased overall survival than unilateral retinoblastoma (96.1% 10-year overall survival). Bilateral retinoblastoma was also associated with an increased incidence of nonocular malignancies (7.8%) compared with unilateral retinoblastoma (1.3%; p < 0.0001). Grade 1 tumours were diagnosed at a younger age (0.94 years) than grade 3 (2.24 years) and grade 4 tumours (2.14 years; p < 0.0001). Lower grade and lower stage tumours were independently associated with increased survival. In multivariate Cox proportional hazards analysis, T stage and laterality were the only covariates that correlated with overall survival. CONCLUSIONS: There appear to be associations between retinoblastoma tumour features such as tumour stage, pathological grade, and laterality with patient characteristics such as age at diagnosis, overall survival, and second malignancies.

Retinal Oximetry and Vessel Diameter Measurements With a Commercially Available Scanning Laser Ophthalmoscope in Diabetic Retinopathy.

Purpose: To test the hypothesis that retinal vascular diameter and hemoglobin oxygen saturation alterations, according to stages of diabetic retinopathy (DR), are discernible with a commercially available scanning laser ophthalmoscope (SLO). Methods: One hundred eighty-one subjects with no diabetes (No DM), diabetes with no DR (No DR), nonproliferative DR (NPDR), or proliferative DR (PDR, all had photocoagulation) underwent imaging with an SLO with dual lasers (532 nm and 633 nm). Customized image analysis software determined the diameters of retinal arteries and veins (DA and DV) and central retinal artery and vein equivalents (CRAE and CRVE). Oxygen saturations of hemoglobin in arteries and veins (SO2A and SO2V) were estimated from optical densities of vessels on images at the two wavelengths. Statistical models were generated by adjusting for effects of sex, race, age, eye, and fundus pigmentation. Results: DA, CRAE, and CRVE were reduced in PDR compared to No DM (P ≤ 0.03). DV and CRVE were similar between No DM and No DR, but they were higher in NPDR than No DR (P ≤ 0.01). Effect of stage of disease on SO2A differed by race, being increased relative to No DM in NPDR and PDR in Hispanic participants only (P ≤ 0.02). Relative to No DM, SO2V was increased in NPDR and PDR (P ≤ 0.05). Conclusions: Alterations in retinal vascular diameters and SO2 by diabetic retinopathy stage can be detected with a widely available SLO, and covariates such as race can influence the results.

Pupillary responses in non-proliferative diabetic retinopathy.

The goal of this study was to determine the extent of rod-, cone-, and melanopsin-mediated pupillary light reflex (PLR) abnormalities in diabetic patients who have non-proliferative diabetic retinopathy (NPDR). Fifty diabetic subjects who have different stages of NPDR and 25 age-equivalent, non-diabetic controls participated. PLRs were measured in response to full-field, brief-flash stimuli under conditions that target the rod, cone, and intrinsically-photosensitive (melanopsin) retinal ganglion cell pathways. Pupil responses were compared among the subjects groups using age-corrected linear mixed models. Compared to control, the mean baseline pupil diameters were significantly smaller for all patient groups in the dark (all p < 0.001) and for the moderate-severe NPDR group in the light (p = 0.003). Pairwise comparisons indicated: (1) the mean melanopsin-mediated PLR was significantly reduced in the mild and moderate-severe groups (both p < 0.001); (2) the mean cone-mediated PLR was reduced significantly in the moderate-severe group (p = 0.008); (3) no significant differences in the mean rod-mediated responses. The data indicate abnormalities in NPDR patients under conditions that separately assess pupil function driven by different photoreceptor classes. The results provide evidence for compromised neural function in these patients and provide a promising approach for quantifying their neural abnormalities.

The Effects of Diabetic Retinopathy Stage and Light Flicker on Inner Retinal Oxygen Extraction Fraction.

PURPOSE: We determined the effects of light flicker and diabetic retinopathy (DR) stage on retinal vascular diameter (D), oxygen saturation (SO2), and inner retinal oxygen extraction fraction (OEF). METHODS: Subjects were categorized as nondiabetic control (NC, n = 42), diabetic with no clinical DR (NDR; n = 32), nonproliferative DR (NPDR; n = 42), or proliferative DR (PDR; n = 14). Our customized optical imaging system simultaneously measured arterial and venous D (DA, DV) and SO2 (SO2A, SO2V) before and during light flicker. Inner retinal OEF was derived from SO2 values. Light flicker-induced ratios of metrics (DAR, DVR, SO2AR, SO2VR, OEFR) were calculated. RESULTS: Arterial D was larger in NPDR compared to NC (P = 0.01) and PDR (P = 0.002), whereas DV was similar among groups (P ≥ 0.16). Light flicker increased DA and DV (P ≤ 0.004), but DAR and DVR were similar among groups (P ≥ 0.09). Arterial SO2 was higher in all groups compared to NC (P ≤ 0.02) and higher in PDR compared to NDR and NPDR (P<0.001). Arterial SO2 did not change with light flicker (P ≥ 0.1). Venous SO2 was higher in NPDR and PDR compared to NC and NDR (P ≤ 0.02). Light flicker increased SO2V in NC, NDR, and PDR (P ≤ 0.003), and SO2VR was lower in NPDR compared to NC and NDR (P ≤ 0.05). Inner retinal OEF was lower in NPDR compared to NDR and PDR (P ≤ 0.02). Light flicker decreased OEF (P ≤ 0.03), but OEFR was greater in NPDR compared to NC and NDR (P ≤ 0.03). CONCLUSIONS: The findings of alterations in retinal D, SO2, OEF, and their light flicker-induced responses at stages of DR may be useful to elucidate the pathophysiology of DR.

Alterations in Retinal Layer Thickness and Reflectance at Different Stages of Diabetic Retinopathy by En Face Optical Coherence Tomography.

PURPOSE: This article reports a method for en face optical coherence tomography (OCT) imaging and quantitative assessment of alterations in both thickness and reflectance of individual retinal layers at different stages of diabetic retinopathy (DR). METHODS: High-density OCT raster volume scans were acquired in 29 diabetic subjects divided into no DR (NDR) or non-proliferative DR (NPDR) groups and 22 control subjects (CNTL). A customized image segmentation method identified eight retinal layer interfaces and generated en face thickness maps and reflectance images for nerve fiber layer (NFL), ganglion cell and inner plexiform layers (GCLIPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), photoreceptor outer segment layer (OSL), and retinal pigment epithelium (RPE). Mean thickness and intensity values were calculated in nine macular subfields for each retinal layer. RESULTS: En face thickness maps and reflectance images of retinal layers in CNTL subjects corresponded to normal retinal anatomy. Total retinal thickness correlated negatively with age in nasal subfields (R ≤-0.31; P ≤ 0.03, N = 51). In NDR subjects, NFL and OPL thickness were decreased (P = 0.05), and ONL thickness was increased (P = 0.04) compared to CNTL. In NPDR subjects, GCLIPL thickness was increased in perifoveal subfields (P< 0.05) and INL intensity was higher in all macular subfields (P = 0.04) compared to CNTL. CONCLUSIONS: Depth and spatially resolved retinal thickness and reflectance measurements are potential biomarkers for assessment and monitoring of DR.