Angela Tindara Sframeli

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.

A new counter-intuitive therapy for adult amblyopia

Visual cortex plasticity is high during a critical period of early postnatal development, but rapidly diminishes with the transition to adulthood. Accordingly, visual disorders such as amblyopia (lazy eye), can be treated early in life by long-term occlusion of the non-amblyopic eye, but may become irreversible in adults, because of the decline in brain plasticity. Here we show that a novel counter-intuitive approach can promote the recovery of visual function in adult amblyopic patients: short-term occlusion of the amblyopic (not the fellow) eye, combined with physical exercise (cycling). After six brief (2h) training sessions, visual acuity improved in all ten patients (0.15±0.02 LogMar), and six of them also recovered stereopsis. The improvement was preserved for up to one year after training. A control experiment revealed that physical activity was crucial for the recovery of visual acuity and stereopsis. Thus, we propose a non-invasive therapeutic strategy for adult human amblyopia based an inverse-occlusion and physical exercise procedure.Visual cortex plasticity is high during a critical period of early postnatal development, but rapidly diminishes with the transition to adulthood. Accordingly, visual disorders such as amblyopia (lazy eye), can be treated early in life by long-term occlusion of the non-amblyopic eye, but may become irreversible in adults, because of the decline in brain plasticity. Here we show that a novel counter-intuitive approach can promote the recovery of visual function in adult amblyopic patients: short-term occlusion of the amblyopic (not the fellow) eye, combined with physical exercise (cycling). After six brief (2h) training sessions, visual acuity improved in all ten patients (0.15+-0.02 LogMar), and six of them also recovered stereopsis. The improvement was preserved for up to one year after training. A control experiment revealed that physical activity was crucial for the recovery of visual acuity and stereopsis. Thus, we propose a non-invasive therapeutic strategy for adult human amblyopia based an inverse-occlusion and physical exercise procedure.

A case of drug-induced Graves’ Orbitopathy after combination therapy with Tremelimumab and Durvalumab

The new frontier of cancer therapy is based on anti-tumor agents against immune checkpoints [1]. We report a case of Graves’ Orbitopathy (GO) in a patient treated with Tremelimumab and Durvalumab. A 70-year-old man was diagnosed with an advanced lung adenocarcinoma and enrolled in a Phase III study on non small-cell lung cancer (ClinicalTrials.gov no. NCT02453282). He was given Durvalumab plus Tremelimumab, but 1 month later diplopia appeared. Thyroid tests showed a primary hypothyroidism, a condition that can be associated with GO [3, 4]. Anti-tumor treatment was discontinued and l-thyroxine started. He was given prednisone 25 mg/day, which was tapered to withdrawal with no apparent benefits. Six months later the patient came to our observation. He had a bilateral orbitopathy with primary gaze diplopia. Exophthalmometry was 20 mm in both eyes with a clinical activity score of 2/7 points (mild palpebral edema and conjunctival redness). There was a reduction of eye motility in all directions. Anti-TSH receptor autoantibodies (TRAb) were detectable (1.42 U/L; NV ≤ 0.55). An orbital MRI showed an enlargement of extraocular muscles, especially the inferior and medial rectus. We concluded for “moderately severe, slightly active GO”. The case suggests a possible relation between anti-tumor therapies and GO. Immunomodulating antibodies act by suppressing immune-evading mechanisms used by tumor cells [1]. Tremelimumab is a human monoclonal antibody against cytotoxic T lymphocyte antigen-4 (CTLA-4). Anti-CTLA-4 antibodies increase T-cell function and anti-tumor responses. Durvalumab is a human monoclonal antibody against the programmed death protein-1 (PD-1) [1]. Durvalumab blocks the interaction of PD-ligand 1 (PD-L1) with PD-1, a T-cell receptor similar to CTLA-4, which is effective in several solid cancers. Inhibition of CTLA-4 induces a syndrome with autoimmune or auto-inflammatory side-effects, designated as “immune-related adverse events”, including colitis/ diarrhea, dermatitis, hepatitis, and endocrinopathies. These effects are generally mild, reversible, and manageable. To our knowledge, there were no previous reports of de novo appearance of GO after anti-tumor therapies targeting immune checkpoints. However, a case of drug-induced myopathy involving extraocular muscles after Tremelimumab and Durvalumab was reported [2]. The patient developed diplopia, ptosis, fatigue, and weakness. The authors concluded that the cause was an inflammatory myopathy affecting extraocular muscles. Apparently, thyroid function and TRAb were not evaluated, or at least not reported. Thus, it is not possible to exclude that the patient had a GO, although palpebral ptosis militates against a diagnosis of GO. It is reasonable to postulate that the mechanisms by which immune therapies induced GO should not differ from those of the other anti-CTLA-4-induced autoimmune diseases [2]. CTLA-4 provides a negative signal to T-cells, thereby acting on immune response and tolerance [1]. Breakdown of tolerance may result in induction of autoimmunity. Obviously, we could not establish to what extent Tremelimumab and Durvalumab contributed the occurrence of GO and which * M. Marinò michele.marino@med.unipi.it

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.