Effects of circadian rhythm disruption on retinal physiopathology: Considerations from a consensus of experts.

The circadian rhythms originate within the organism and synchronize with cyclic fluctuations in the external environment. It has been demonstrated that part of the human genome is under control of the circadian clock and that a synchronizer that helps to maintain daily rhythms is Melatonin, a neuro-hormone primarily synthesized by the pineal gland during the night. The chronic disruption of circadian rhythm has been linked to many conditions such as obesity, metabolic syndrome, type 2 diabetes, cancer, and neurodegenerative diseases. Studies in the mice showed that the disruption of the retinal circadian rhythm increases the decline during the aging of photoreceptors, accelerating age-related disruption of cone cell structure, function, and viability and that the melatonin receptor deletion seems to influence the health of retinal cells, speeding up their aging. In conclusion, preserving the circadian rhythms could be to add to the prevention and treatment of age-related degenerative retinal diseases, and although additional studies are needed, melatonin could be a valid support to favor this "chronoprotection action".

High glucose induces an early and transient cytoprotective autophagy in retinal Müller cells.

PURPOSE: We investigated the autophagic response of rat Müller rMC-1 cells during a short-term high glucose challenge. METHODS: rMC-1 cells were maintained in 5 mM glucose (LG) or exposed to 25 mM glucose (HG). Western blot analysis was used to evaluate the expression levels of markers of autophagy (LC3-II, p62) and glial activation (AQP4), as well as the activation of TRAF2/JNK, ERK and AKT pathways. Autophagic flux assessment was performed using the autophagy inhibitor chloroquine. ROS levels were measured by flow cytometry using dichlorofluorescein diacetate. ERK involvement in autophagy induction was addressed using the ERK inhibitor FR180204. The effect of autophagy inhibition on cell viability was evaluated by SRB assay. RESULTS: Activation of autophagy was observed in the first 2-6 h of HG exposure. This early autophagic response was transient, not accompanied by an increase in AQP4 or in the phospho-activation of JNK, a key mediator of cellular response to oxidative stress, and required ERK activity. Cells exposed to HG had a lower viability upon autophagy inhibition by chloroquine, as compared to those maintained in LG. CONCLUSION: A short-term HG challenge triggers in rMC-1 cells a process improving the ability to cope with stressful conditions, which involves ERK and an early and transient autophagy activation.

Outer retina dysfunction and choriocapillaris impairment in type 1 diabetes.

To study the outer retina morpho-functional characteristics and the choriocapillaris (CC) features in type 1 diabetic (T1D) patients, with and without signs of diabetic retinopathy (NPDR and NoDR). Twenty-five NPDR and 18 NoDR eyes were imaged by Optical Coherence Tomography Angiography. Ellipsoid zone (EZ) "normalized" reflectivity and CC perfusion density parameters, as flow deficits number (FDn), flow deficit average area (FDa) and flow deficit percentage (FD%), were analysed. Multifocal electroretinogram (mfERG) response amplitude densities (RADs) were measured. Mean EZ "normalized" reflectivity, CC FDn and FD% values, were similar (p > 0.05) in both groups, FDa was significant greater (p > 0.05) in NPDR compared with NoDR eyes. MfERG-RADs were similar in both groups. NPDR eyes showed a significant (p < 0.05) linear correlation between RADs and both, CC FDa and FD%. The EZ "normalized" reflectivity was negatively correlated with CC FD% in NoDR eyes. In NPDR T1D eyes a significant relationship between abnormal outer retina functional responses and CC impairment was observed, while in NoDR eyes the photoreceptor reflectivity was correlated to CC abnormalities. The outer retina dysfunction in NPDR correlated to CC drop-out let hypothesize that the outer retinal elements are functionally impaired in proportion to the CC vascular supply deficit.

Optical coherence tomography analysis of evolution of Bruch's membrane features in angioid streaks.

PurposeTo describe optical coherence tomography (OCT) features in the Bruch's membrane (BM) of eyes with angioid streaks (AS) and evaluate their evolution over the follow-up.Patients and methodsPatients with AS presenting between March 2016 and September 2016 at two tertiary referral centers were consecutively recruited in this study. Eligibility criteria included prior spectral domain (SD)-OCT images, taken at least 3 months before at the same referral center, with automated eye tracking and image alignment modules. Alterations of BM were described and compared to previous scans over the follow-up. Multimodal imaging was used to identify alteration of retinal pigment epithelium (RPE) and choroid.ResultsThirty-two eyes of 16 consecutive patients with AS were included. BM undulations, mostly observed around the optic nerve head, were found in 19 (59.4%) of 32 eyes. BM breaks were found in 31 (96.9%) out of 32 eyes. Evolution of BM undulations into BM breaks was observed in 5 eyes (15.6%). Choroidal neovascularization (CNV) was observed in 12 eyes (37.5%) during follow-up, typically in areas of BM interruption.ConclusionsBM undulations, probably caused by high stretching forces exerted on the BM around the optic nerve head, seem to precede some BM breaks. BM interruptions may be a preferred way for the growth of CNV, which was identified in one-third of our cases.

Aflibercept in persistent neovascular AMD: comparison of different treatment strategies in switching therapy.

PurposeTo evaluate the effects of aflibercept administered according to a pro re nata (PRN) or Fixed Regimen to patients with neovascular AMD and persistent intraretinal/subretinal fluid (IRF/SRF) despite three consecutive ranibizumab injections.MethodsPatients were switched to aflibercept injection (IVA) administered according to a PRN or to a fixed regimen for 1 year in two different retina centers. At baseline each patient underwent a complete ophthalmologic evaluation, including best-corrected visual acuity assessment (BCVA ETDRS chart), fluorescein, and indocyanine green angiography and OCT.ResultsEach group included 36 eyes. After 1 year the PRN group showed BCVA stabilization (63 vs 60 letters, P=0.33), whereas fixed regimen group showed significant BCVA improvement (68 vs 71, P=0.008). The median central retinal thickness decreased by 94 µm in the PRN (P=0.002) and by 148 µm in the fixed regimen group (P≤0.001). Complete IRF/SRF reabsorption was found in 58% of eyes in the PRN and in 42% of eyes in the fixed regimen group. At 1-year visit, the percentage of eyes with pigment epithelium detachment did not significantly decrease, but a height reduction was recorded in both groups. The median number of IVA was 3.5 in the PRN and 7 in the fixed regimen group.ConclusionThe switch to aflibercept with both treatment strategies enabled improvement in morphological parameters and stabilization of visual acuity. BCVA improvement and reduction in vision loss with reduction in retinal thickness, fluid and PED height was achieved with the fixed regimen in previously treated nAMD after 1 year.

Choroidal neovascularization in angioid streaks and pseudoxanthoma elasticum: 1 year follow-up.

PURPOSE: To report the efficacy of intravitreal injection of bevacizumab 1.25 mg (IVB) in the treatment of choroidal neovascularization (CNV) secondary to angioid streaks (AS). METHODS: Case review of two patients with CNV secondary to AS treated with three IVB with a 1-year follow up. RESULTS: In both patients after 1 year fluorescein angiography and optical coherence tomography showed complete inactivity of the CNV and the ophthalmologic examination revealed stabilization of the visual acuity. CONCLUSIONS: The IBV appeared to be an effective and safe treatment for CNV secondary to AS resulting in a long-term CNV inactivation. Further long-term studies in this type of lesion are desirable.

The role of Humphrey Matrix testing in the early diagnosis of retinopathy in type 1 diabetes.

AIM: The aim of the study was to investigate the role of Humphrey Matrix threshold testing in the detection of early functional retinal impairment in subjects with type 1 diabetes mellitus (DM1) without any signs of retinal vasculopathy, and to investigate the relationship between both functional and structural retinal parameters and metabolic control. METHODS: Thirty eyes of 30 subjects with DM1, with no sign of retinal vasculopathy, and 30 eyes of 30 age- and sex-matched healthy subjects were enrolled in this cross-sectional clinical study. Functional testing included Humphrey Matrix perimetry and white-on-white Humphrey visual field perimetry (HFA), while retinal nerve fibre layer (RNFL) thickness was measured by scanning laser polarimetry with variable corneal birefringence compensator (GDx VCC). RESULTS: Matrix mean deviation (MD) was found to be significantly reduced in subjects with DM1 compared with controls (-1.10 (SD 2.98; 95% CI -2.21 to 0.01) vs 1.37 (SD 2.11; 95% CI 0.58 to 2.16), p = 0.0005). HFA MD and pattern standard deviation (PSD) were significantly worse in subjects with DM1 compared with controls (p = 0.010 and p = 0.013 respectively). Among structural parameters, average peripapillary RNFL thickness was reduced in DM1 subjects (p = 0.006). Matrix MD and HFA MD and PSD, and average peripapillary and superior RNFL, were significantly reduced in subjects with DM1 with HbA(1c) > or = 7% compared with controls. CONCLUSIONS: Functional and structural retinal testing by Humphrey Matrix and GDx VCC could be useful for the identification of early retinal impairment in people with DM1 with no sign of retinal vasculopathy.

Rheopheresis in vascular diseases.

BACKGROUND: Endothelial dysfunction is a common condition in many microvascular diseases, such as Age-related Macular Degeneration (AMD) and Peripheral Arterial Occlusive Disease (PAOD). Rheopheresis therapy improves ematic viscosity, shear stress and endothelial function while decreasing fibrinogen, LDL-cholesterol and alpha-2-macroglobulin levels. OBJECTIVE: To evaluate the therapeutic efficacy of rheopheresis in patients with microcirculatory diseases. MATERIALS AND METHODS: Eight patients (7 male and 1 female) were treated with rheopheresis: 3 males were affected by AMD, 4 male and 1 female by uremia and PAOD. We used Membrane Differential Filtration (MDF) with an ethinylvinyl alcohol copolymer membrane as plasmafiltrator. Patients with AMD were treated once a week for ten weeks. Patients affected with PAOD were treated twice weekly for 3 weeks and then were placed on a once-a-week program. RESULTS: In all treated patients with AMD, visual acuity improved. In all patients affected with PAOD, we observed a complete resolution of pain; 3 out of 5 had a complete remission of ulcers. There was partial reduction of ulcers in the other patients and no adverse effects were observed. CONCLUSION: Rheopheresis is a safe, effective form of hemorheotherapy.

Reliability of the IOLMaster in axial length evaluation in silicone oil-filled eyes.

PURPOSE: To assess the reliability of IOLMaster in axial length (AL) measurement in phakic silicone oil-filled vs pseudophakic saline-filled eyes. METHODS: Ten eyes of 10 patients, vitrectomized with silicone oil tamponade and scleral buckled with significant lens opacity were enrolled. Optical biometry with IOLMaster (Carl Zeiss Meditec AG, Germany) was performed 1 day before and 1 week after silicone oil removal and phacoemulsification with artificial intraocular lens (IOL) implantation in order to assess changes in AL measurements. RESULTS: Mean AL was 26.16+/-1.23 mm (range 24.64-28.8 mm) and 26.27+/-1.46 mm (range 25.26-29.6 mm), respectively, the day before and 1 week after silicone oil removal and cataract surgery, and the difference was not statistically significant (P=0.2). CONCLUSIONS: Presence vs absence of silicone oil tamponade as well as phakic vs pseudophakic status in buckled and vitrectomized eyes did not influence the AL measurement by means of no-contact optical biometry, suggesting that such eyes might be candidate for silicone oil removal and cataract surgery at one time.

Argon laser trabeculoplasty in triamcinolone acetonide induced ocular hypertension refractory to maximal medical treatment.

PURPOSE: To report two cases of intraocular hypertension after intravitreal injection of triamcinolone acetonide (iTAA) that were refractory to maximal medical therapy and were successfully treated with argon laser trabeculoplasty (ALT). METHODS: Two patients with history of primary open angle glaucoma were treated with intravitreal injection of triamcinolone acetonide for chronic macular edema secondary to branch retinal vein occlusion. Both patients (Case 1 after 2 months and Case 2 after 5 days) developed intraocular hypertension that did not respond to maximal medical therapy. Despite medical therapy, intraocular pressure (IOP) was 45 mmHg in Case 1 and between 34 and 37 mmHg in Case 2. ALT was performed in the inferior 180 degrees angle using the following parameters: 50 microm size, 700 mW, 0.50 sec, 100 spots. RESULTS: In both patients IOP returned to normal level a few days after ALT. CONCLUSIONS: ALT seems to be effective at reducing IOP in patients with intraocular hypertension secondary to iTAA that does not respond to maximal medical treatment.

Corneal birefringence changes after laser assisted in situ keratomileusis and their influence on retinal nerve fibre layer thickness measurement by means of scanning laser polarimetry.

AIM: To evaluate changes in corneal polarisation properties and their influence on peripapillary retinal nerve fibre layer (RNFL) thickness measurements after laser assisted in situ keratomileusis (LASIK) by means of scanning laser polarimetry (SLP) with variable corneal polarisation compensator (VCC) in normal white subjects. METHODS: SLP was performed by means of GDx VCC on 32 eyes of 32 normal subjects who underwent LASIK for ametropia correction. Corneal polarisation axis and magnitude and RNFL thickness were measured before and 8 days after LASIK. RNFL thickness data and corneal polarimetric data of one randomly selected eye per subject were analysed by the Wilcoxon signed ranks test. Correlations between corneal ablation depth, corneal polarimetric changes, and RNFL thickness changes were investigated using Spearman's rho test. RESULTS: The corneal polarisation axis significantly shifted from 15.1 degrees (17.0 degrees ) to 6.9 degrees (12.9 degrees ) (p = 0.00006) after LASIK and this change showed a strong correlation with corneal ablation depth (rho = -0.7, p = 0.00002). Among GDx parameters, TSNIT, SUP, and SD showed significant changes after LASIK and for SUP and SD these changes were well correlated with the shift in corneal polarisation axis (rho = 0.54, p = 0.03 and rho = 0.45, p = 0.01, respectively). SUP and SD changes were neutralised after compensating for corneal polarimetric changes but not TSNIT changes. NFI, a discriminating parameter, was found to be affected after LASIK only after compensating for corneal polarimetric changes. CONCLUSIONS: LASIK induces a shift in corneal polarisation axis which is responsible for inaccuracies in RNFL thickness measurements. A customised compensation for corneal polarimetric changes after LASIK allows normalisation of some of the thickness parameters except for TSNIT and NFI.

Pilot study to evaluate the efficacy and safety of pneumatic trabeculoplasty in glaucoma and ocular hypertension.

PURPOSE: Following laser-assisted in situ keratomileusis (LASIK), intraocular pressure (IOP) is measurably lower in a significant number of cases. It has been proposed that the decrease in IOP may be a real event. Prior trials have evaluated pneumatic trabeculoplasty (PNT) in combination with concomitant glaucoma medications. The aim of this study was to determine the efficacy and the safety of PNT alone to lower IOP in patients with primary open angle glaucoma (POAG) or ocular hypertension (OH). METHODS AND RESULTS: A total of 37 subjects with POAG or OH were enrolled in a prospective, open-label, fellow-eye, multicenter trial to determine the IOP lowering effects of PNT. All subjects underwent ophthalmologic examinations and IOP measurements and were washed out from all glaucoma medications prior to the start of the study. The trial was intrapatient controlled for the first 30 days, with one eye receiving PNT at days 0 and 7 and the fellow eye serving as the control. The second eye was treated with PNT at day 30. The patients were followed for 120 days, with the first eye receiving an additional PNT treatment at days 90 and 97. Two analyses-an intent to treat analysis in which the last IOP measurement for patients dropped from the study was carried forward and an analysis including only those patients who completed the trial-were performed. Of the 37 patients enrolled, 27 (73%) completed the study. For the intent to treat analysis the baseline mean IOP was 24.7+/-1.9 mmHg for eye 1 and 23.6+/-2.3 mmHg for eye 2 and the difference was statistically significant (p<0.05). Using this analysis the differences between eye 1 mean IOP at days 1, 7, 14, and 60 and the baseline mean IOP were statistically significant (p<0.05). The differences between eye 2 mean IOP and the baseline mean IOP were statistically significant (p<0.05) at all time points except day 14 and day 30. The greater mean IOP reductions from the baseline mean IOP for eye 1 were at study day 1 (-16,1%), day 14 (-9%), and day 60 (-8.9%). For eye 2 they were at day 60 (-8.7%) and at day 120 (-9.1%). For the analysis that included only those subjects who completed the trial the decrease in eye 1 mean IOP from baseline was statistically significant (p<0.05) at all time points. The decrease in eye 2 mean IOP from baseline was statistically significant at all time points except day 30. Using this analysis the greater mean IOP reductions from the baseline mean IOP for eye 1 were at study day 1 (-19%), day 14 (-15.7%), day 37 (-16.3%), day 60 (-20.0%), day 90 (-18.1%), day 97 (-16.8%), and day 120 (-15.8%). For eye 2 greater mean IOP reductions from baseline mean IOP were seen on day 37 (-13.0%), day 60 (-16.7%), day 90 (-15.5%), day 97 (-14.5%), and day 120 (-7.2%). No statistically significant differences were found in mean IOP reduction between the two eyes treated. A total of 34 patients (92%) showed adverse effects: conjunctival hyperemia in 26 (70.3%) and conjunctival hemorrhage in 14 (37.8%). CONCLUSIONS: This pilot study of PNT showed a potentially good IOP lowering effect on glaucoma and hypertensive patients. Additional studies would help to better define the types of patients who respond to PNT and to identify risk factors that may lead to treatment failure.