Retinal, choroidal and optic disc analysis in patients with Graves' disease with or without orbitopathy.

PURPOSE: To compare optic disc, retinal and choroidal measurements in patients with Graves' disease with or without orbitopathy, and healthy controls. METHODS: Optical coherence tomography and Heidelberg retinal tomography were performed in 40 patients with Graves' orbitopathy (GO), 40 subjects with Graves's disease (GD) with no sign of orbitopathy and 40 healthy controls. Degree of exophthalmos, ocular alignment, clinical activity score (CAS), choroidal thickness, retinal thickness, ganglion cell layer (GCL) thickness, disc area, cup area, rim area, cup/disc area ratio, linear cup/disc ratio and mean peripapillary retinal nerve fibre layer thickness were analysed. RESULTS: GO patients and healthy controls significantly differ regarding mean central retinal thickness (275 ± 19 µm and 285 ± 20 µm, P = 0.017); mean central GCL thickness (14.87 ± 3.0 µm and 17.92 ± 5.02 µm, P = 0.001); mean disc area (2.00 ± 0.44 mm2 and 1.72 ± 0.37 mm2, P = 0.003); mean cup area (0.53 ± 0.52 mm2 and 0.31 ± 0.20 mm2, P = 0.003); cup/disc area ratio (0.22 ± 0.10 and 0.17 ± 0.08, P = 0.010); and linear cup/disc ratio (0.47 ± 0.15 and 0.40 ± 0.13, respectively, P = 0.011). No difference was found between patients without orbitopathy and healthy controls. No significant difference was found regarding the choroidal thickness between the three groups. There was no statistically significant relationship between retinal thickness, ganglion cell layer thickness, mean disc area, mean cup area, cup/disc area ratio, linear cup/disc ratio, CAS, exophthalmometric value and ocular alignment. CONCLUSION: GO patients showed significant changes in foveal and GCL thickness, and optic nerve head morphology suggesting a possible influence of the orbital inflammatory process.

Macular spectral-domain optical coherence tomography values and correlations in healthy children.

PURPOSE: The aim of this study is to investigate potential correlations between age, gender, spherical equivalent and optical coherence tomography (OCT) retinal parameters among healthy children. METHODS: A macular spectral-domain OCT was performed in all patients using a Spectralis® OCT device, and the macular thickness and volume of each of the early treatment diabetic retinopathy study (ETDRS) subfields were analysed. RESULTS: Ninety-four children were enrolled. Mean central macular thickness was 274.968 ± 18.28 µm, while mean central macular volume was 0.216 mm3. Statistical analysis showed a significant correlation between the factor age and central macular thickness (F(3,90) = 4.96, p = 0.003, η2 = 0.14) and central macular volume (F(3,90) = 4.98, p = 0.003, η2 = 0.14). Statistical analysis showed a significant correlation between the factor gender and macular thickness/volume of several ETDRS subfields. A significant correlation between refractive error and macular thickness/volume was also noted. CONCLUSIONS: This study shows significant correlations between macular thickness/volume and the factors age, gender and spherical equivalent. Paediatric spectral-domain optical coherence tomography ranges need further investigations since many significant correlations are still to be confirmed.

Statins for Graves' orbitopathy (STAGO): a phase 2, open-label, adaptive, single centre, randomised clinical trial.

BACKGROUND: A protective action of statins on development of Graves' orbitopathy suggests that statins might be used for treatment of the disease. We aimed to assess the efficacy of the addition of a statin, atorvastatin, to intravenous glucocorticoids (ivGCs) on Graves' orbitopathy outcomes in patients with hypercholesterolaemia. METHODS: We did a randomised, open-label, phase 2, adaptive, clinical trial at a single, tertiary, referral hospital in Pisa, Italy. Patients with moderate-to-severe, active Graves' orbitopathy, with a low-density lipoprotein cholesterol concentration between 2·97 and 4·88 mmol/L were eligible for inclusion. Patients were randomly assigned (1:1) in 11 blocks of eight, using a computer-based system, to the ST group or the NST group. The ST group received ivGCs (methylprednisolone 500 mg once a week for 6 weeks followed by 250 mg once a week for an additional six weeks) for 12 weeks and oral atorvastatin (20 mg once a day) for 24 weeks. The NST group only received the ivGC regimen. Patients were unmasked to group allocation; however, the ophthalmological investigator was masked to randomisation. The primary endpoint was the Graves' orbitopathy outcome (composite evaluation of exophthalmos, clinical activity score, eyelid aperture, and diplopia) at 24 weeks in the modified intention-to-treat (ITT) population (patients who attended the week 12 visit). Patients were considered responders when at least two of the following criteria were fulfilled in the most affected eye, without worsening in any of the same measures in both eyes: (1) reduction in exophthalmos of 2 mm or more, with no increase by 2 mm or more in the other eye; (2) reduction of clinical activity score by two or more points; (3) reduction in eyelid aperture by 2 mm or more, with no increase by 2 mm or more in the other eye; and (4) disappearance or improvement (change from constant to inconstant, intermittent, or absent, or from inconstant to intermittent or absent) of diplopia, and (5) improvement in visual acuity by 0·2 decimals or more. The trial is registered with EUDRACT, 2018-001317-33, and ClinicalTrials.gov, NCT03110848. FINDINGS: Between June 1, 2020, and Nov 30, 2020, 119 patients were screened for inclusion, of whom 88 (74%) patients were enrolled and randomly assigned to one of the two treatment groups (44 [50%] to the ST group and 44 [50%] to the NST group). Eight (9%) patients did not attend the 12 week visit; 80 (91%) patients (18 [23%] men and 62 [78%] women) were included in the modified ITT population (41 [51%] in the ST group and 39 [49%] in the NST group]. The proportion of Graves' orbitopathy composite evaluation responders at 24 weeks was higher in the ST group (21 [51%] of 41 patients) than the NST group (11 [28%] of 39 patients; attributable risk 0·23 [95% CI 0·02-0·44]; p=0·042). 26 adverse events occurred in 21 (24%) of 88 patients in the safety population. One (2%) of 44 patients in each group required treatment discontinuation, with no serious adverse events and no difference between groups. INTERPRETATION: Addition of oral atorvastatin to an ivGC regimen improved Graves' orbitopathy outcomes in patients with moderate-to-severe, active eye disease who were hypercholesterolaemic. Future phase 3 studies, which could potentially recruit patients regardless of low-density lipoprotein cholesterol concentration, are required to confirm this association. FUNDING: Associazione Allievi Endocrinologia Pisana.

Genetic Profiling of Orbital Fibroblasts from Patients with Graves' Orbitopathy.

CONTEXT: Graves' orbitopathy (GO) is an autoimmune disease that persists when immunosuppression is achieved. Orbital fibroblasts from GO patients display peculiar phenotypes even if not exposed to autoimmunity, possibly reflecting genetic or epigenetic mechanisms, which we investigated here. OBJECTIVE: We aimed to explore potential genetic or epigenetic differences using primary cultures of orbital fibroblasts from GO and control patients. METHODS: Cell proliferation, hyaluronic acid (HA) secretion, and HA synthases (HAS) were measured. Next-generation sequencing and gene expression analysis of the whole genome were performed, as well as real-time-PCR of selected genes and global DNA methylation assay on orbital fibroblasts from 6 patients with GO and 6 control patients from a referral center. RESULTS: Cell proliferation was higher in GO than in control fibroblasts. Likewise, HA in the cell medium was higher in GO fibroblasts. HAS-1 and HAS-2 did not differ between GO and control fibroblasts, whereas HAS-3 was more expressed in GO fibroblasts. No relevant gene variants were detected by whole-genome sequencing. However, 58 genes were found to be differentially expressed in GO compared with control fibroblasts, and RT-PCR confirmed the findings in 10 selected genes. We postulated that the differential gene expression was related to an epigenetic mechanism, reflecting diverse DNA methylation, which we therefore measured. In support of our hypothesis, global DNA methylation was significantly higher in GO fibroblasts. CONCLUSIONS: We propose that, following an autoimmune insult, DNA methylation elicits differential gene expression and sustains the maintenance of GO.

Cannabinoids in Glaucoma Patients: The Never-Ending Story.

Glaucoma is one of the principal causes of irreversible blindness worldwide. Yet, intraocular pressure (IOP) is the main modifiable risk factor for disease progression. In the never-ending challenge to develop new and effective drugs, several molecules have been tested as anti-glaucoma agents thanks to their pressure-lowering capabilities. Among these molecules, the cannabinoids have been investigated as possible anti-glaucoma drugs since the early 1970s. Cannabinoids are a large class of chemical compounds that exploit their effects by interaction with cannabinoid receptors 1 and 2. These receptors are widely expressed in the human retina where they may influence important functions such as photo-transduction, amacrine cell network maintenance, and IOP regulation. Therefore, in past years several studies have been conducted in order to assess the IOP lowering effects of cannabinoids. PRISMA guidelines have been used to perform a literature search on Pubmed and Scopus aiming to investigate the mechanism of IOP lowering effects and the potential benefits of orally administered, inhaled, topical, and intravenous cannabinoids in the treatment of glaucoma patients.

A new counterintuitive training for adult amblyopia.

Objectives: The aim of this study was to investigate whether short-term inverse occlusion, combined with moderate physical exercise, could promote the recovery of visual acuity and stereopsis in a group of adult anisometropic amblyopes. Methods: Ten adult anisometropic patients underwent six brief (2 h) training sessions over a period of 4 weeks. Each training session consisted in the occlusion of the amblyopic eye combined with physical exercise (intermittent cycling on a stationary bike). Visual acuity (measured with ETDRS charts), stereoacuity (measured with the TNO test), and sensory eye dominance (measured with binocular rivalry) were tested before and after each training session, as well as in follow-up visits performed 1 month, 3 months, and 1 year after the end of the training. Results: After six brief (2 h) training sessions, visual acuity improved in all 10 patients (0.15 ± 0.02 LogMar), and six of them also recovered stereopsis. The improvement was preserved for up to 1 year after training. A pilot experiment suggested that physical activity might play an important role for the recovery of visual acuity and stereopsis. Conclusions: Our results suggest a noninvasive training strategy for adult human amblyopia based on an inverse-occlusion procedure combined with physical exercise.

Association of T and B Cells Infiltrating Orbital Tissues With Clinical Features of Graves Orbitopathy.

Importance: Graves orbitopathy (GO) responds to immunosuppressive treatments when clinically active but poorly when inactive. In other autoimmune diseases, response has been ascribed to a reduction in lymphocytes infiltrating the target organ. It is not known whether active vs inactive GO differs in this regard, which would help in understanding the link between GO immunologic features and clinical behavior. Objective: To investigate the association between orbital lymphocytic infiltrate and GO clinical features. Design, Setting, and Participants: A cohort study aimed at assessing the extent and immunohistochemical phenotype of orbital lymphocytes and associating it with the ophthalmologic features of GO, especially its clinical activity score (CAS), was conducted at a tertiary referral center. Twenty consecutive patients with GO who underwent orbital decompression were included. The study was conducted from January 1 to May 31, 2017. Exposures: Orbital tissue histology and immunohistochemistry testing as well as ophthalmologic evaluation. Main Outcomes and Measures: Association between CAS and orbital lymphocytes, analyzed as total number of lymphocytes and main lymphoid subsets. Results: The patient population included 8 men and 12 women, all of white race, with a mean (SD) age of 46 (13) years. With an established cutoff value of 300 lymphoid cells per tissue sample, lymphocytes above this value were found in orbital tissues of 9 of 20 patients (45%), often organized into distinct foci. The lymphocytes comprised a mixture of T (CD3-positive) and B (CD20-positive) cells, suggesting a mature, polyclonal autoimmune response. In a simple linear regression model, the total number of lymphocytes, as well as the number of CD3- and CD20-positive subsets, correlated with CAS (R = 0.63; 95% CI, 0.27-0.84; P = .003; R = 0.59; 95% CI, 0.20-0.82; P = .006; and R = 0.65; 95% CI, 0.30-0.85; P = .002, respectively). In a multiple linear regression model, lymphocytes maintained their effect on CAS when adjusted for 2 additional variables that were correlated with CAS-smoking and GO duration-highlighting even more the important role of orbital lymphocytes in affecting CAS (total number: R = 0.58; 95% CI, 0.18-0.82; P = .01; CD3-positive: R = 0.58; 95% CI, 0.17-0.82; P = .01; and CD20-positive: R = 0.59; 95% CI, 0.19-0.83; P = .01). Conclusions and Relevance: This study shows a correlation between T and B lymphocytes infiltrating orbital tissues and the activity of GO, possibly enhancing our understanding of the association between GO immunologic features and clinical expression.

Late spontaneous resolution of a double anterior chamber post deep anterior lamellar keratoplasty.

A 31-year-old healthy male underwent deep anterior lamellar keratoplasty with big-bubble technique for treatment of keratoconus in his right eye. One week after surgery, he presented with detachment of the endothelium-Descemet complex with formation of a double anterior chamber, despite the apparent absence of an intraoperative Descemet membrane rupture. A subsequent intervention with the intent to relocate the corneal graft button was not effective, because the detachment appeared again one day later. The authors hypothesized that, at the time of the stromal dissection with big bubble technique, a small amount of air penetrated into the anterior chamber, creating a false pathway through the trabecular meshwork. The aqueous humor then penetrated the graft flowing through the false pathway, causing the endothelium-Descemet detachment. The persistence of that pathway, even after the intervention of graft repositioning, caused the failure of the latter procedure and persistence of the double chamber. We decided to wait and observe. The double anterior chamber spontaneously resolved in approximately three months.

The supraciliary space as a suitable pathway for glaucoma surgery: Ho-hum or home run?

The supraciliary space is a physiological route for aqueous humor outflow located anteriorly between the outer surface of the ciliary body and the internal surface of the sclera. Posteriorly, the suprachoroidal space is located between the choroid and the internal surface of the sclera. These spaces have been targeted as suitable and helpful pathways for glaucoma treatment, alternatives to the traditional subconjunctival space. The subconjunctival surgical pathway is affected by several limitations such as poor cosmesis, a lifetime risk for endophthalmitis, and an unpredictable wound healing response. Because of these limitations, the supraciliary space has gained growing interest as a possible target for new glaucoma drainage devices such as: Gold Micro Shunt (SOLX Inc.; Waltham, MA, USA), iStent Supra (Glaukos Corporation, Laguna Hills, CA, USA), CyPass Micro-Stent (Transcend Medical Inc., Menlo Park, CA, USA), Aquashunt (OPKO health Inc., Miami, FL, USA), STARflo (iSTAR Medical, Isnes, Belgium), and Esnoper-Clip implant (AJL Ophthalmics, Álava, Spain). We review the current literature concerning the supraciliary space to evaluate its safety and efficacy as a suitable pathway for glaucoma surgical treatment.

Trabeculectomy Versus EX-PRESS Shunt Versus Ahmed Valve Implant: Short-term Effects on Corneal Endothelial Cells.

PURPOSE: To evaluate short-term changes in corneal endothelial cells after trabeculectomy, EX-PRESS device implantation, and Ahmed valve implantation for the treatment of primary open-angle glaucoma. DESIGN: Prospective, interventional, comparative case series with contralateral eye control study. METHODS: We prospectively evaluated the changes in number, density, and shape of the corneal endothelium cells in 128 eyes of 64 patients divided into 3 groups depending on the treatment received. Corneal specular microscopy was performed with a noncontact specular microscope preoperatively and at 1 and 3 months after surgery. The changes at each time point were compared with those of the control group, which consisted of 32 contralateral glaucomatous eyes receiving antiglaucoma medications without any previous glaucoma surgery. RESULTS: In the subjects who underwent trabeculectomy, corneal endothelial cell density (ECD) significantly decreased by 3.5% (P = .012, paired t test) at 1 month and 4.2% (P = .007) at 3 months after surgery, compared to the baseline values. In the Ahmed valve group ECD did not change at 1 month after surgery and had a significant 3.5% decrease at 3 months (P = .04). In the patients who underwent EX-PRESS implantation and in the control group ECD did not change either at 1 month or at 3 months after surgery (P > .05). CONCLUSIONS: EX-PRESS shunt, compared to trabeculectomy and Ahmed valve, seems to be a safer procedure regarding the risk of endothelial cell loss. For this reason, it may be the treatment of choice in patients with significant low corneal ECD before surgery or other risk factors for corneal damage.