Mammalian target of rapamycin inhibitors for the treatment of astrocytic hamartoma in tuberous sclerosis complex (TSC).

PURPOSE: Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder. Fifty percent of patients with TSC will develop retinal astrocytic hamartoma (RAH). The mammalian target of rapamycin (mTOR) inhibitors interferes with the pathological mechanisms of TSC. Treatment of RAH with mTOR inhibitors has been described in only a few isolated case reports. The purpose of this study was to assess the effect of mTOR inhibitors on RAH in a small cohort of patients. METHODS: The medical records of all consecutive patients with ocular manifestations of TSC that were treated with mTOR inhibitors at the Sheba Medical Center from January 2014 to December 2018 were retrospectively reviewed. Data collection included demographics, medical history, ocular presentation, ocular treatment, and treatment outcome. Tumor size was assessed by a masked observer, before and after treatment. Lesion measurements were made with Heidelberg SD-OCT (HRA + OCT SPECTRALIS), and fundus photos were taken with RetCam3® (Natus, USA) and analyzed by "ImageJ" software. RESULTS: Eleven patients with tuberous sclerosis and astrocytic hamartoma were treated with mTOR inhibitors in the study period. Of them, 6 children (11 eyes, 20 tumors) had proper imaging of tumor size before and after treatment. The analysis included these 11 eyes. All six patients had non-ocular manifestations of TSC, including dermatologic (n = 5), neurologic (n = 5), and renal (n = 3) involvement. Ocular involvement included in five eyes (45%) tumors near the optic disc and in four eyes (37%) foveal tumors. The mean follow-up duration was 2.15 ± 1.4 years (range 10 months to 4.5 years). The average tumor base reduction in the treated group was 17.8% ± 15.9. The average maximal thickness at baseline was 414 ± 174 µm (range 152-686 µm). There was a 14% ± 7.1 reduction after treatment. None of the tumors showed evidence of growth at the final follow-up. CONCLUSION: The findings of this study suggest that mTOR inhibitors can reduce tumor size and that they can be considered as an optional treatment in certain conditions. This preliminary report is the first to quantitatively assess pre- and posttreatment tumor size, in young patients.

Adjuvant therapy of histopathological risk factors of retinoblastoma in Europe: A survey by the European Retinoblastoma Group (EURbG).

INTRODUCTION: Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment. METHOD: Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication. RESULTS: Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy. CONCLUSION: Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers.

UVEITIS AFTER THE BNT162b2 mRNA VACCINATION AGAINST SARS-CoV-2 INFECTION: A Possible Association.

PURPOSE: To describe uveitis cases after the BNT162b2 mRNA SARS-CoV-2 vaccination. METHODS: This is a multicenter, retrospective study. Vaccine-related uveitis diagnosis was supported by the classification of the World Health Organization Adverse Drug Terminology and the Naranjo criteria. RESULTS: Twenty-one patients (23 eyes) with a mean age of 51.3 years (23-78 years) were included. Eight of the 21 patients had a known history of uveitis. The median time from previous to current attack was 1 year (0.5-15 years). There were 21 anterior uveitis cases, two with bilateral inflammation. Eight cases occurred after the first vaccination and 13 after the second vaccination. All but three presented as mild to moderate disease. Two patients developed multiple evanescent white dot syndrome after the second vaccination. The mean time from vaccination to uveitis onset was 7.5 ± 7.3 days (1-30 days). At final follow-up, complete resolution was achieved in all but two eyes, which showed significant improvement. One case of severe anterior uveitis developed vitritis and macular edema after the second vaccination, which completely resolved after an intravitreal dexamethasone injection. CONCLUSION: Uveitis may develop after the administration of the BNT162b2 mRNA vaccine. The most common complication was mild to moderate anterior uveitis, while multiple evanescent white dot syndrome can also occur less frequently.

Chorio-retinal toxoplasmosis: treatment outcomes, lesion evolution and long-term follow-up in a single tertiary center.

BACKGROUND: Ocular toxoplasmosis is a common cause of ocular inflammation worldwide. The aim of this study is to characterize the clinical outcomes and lesion evolution of patients with ocular toxoplasmosis and to compare the primary and reactivation subgroups. METHODS: A retrospective population-based cohort study at one uveitis-specialized tertiary referral center. Patients presenting with active ocular toxoplasmosis between the years 2007-2016 were included. Primary ocular toxoplasmosis and reactivations were compared. RESULTS: Included were 22 patients, 64% female with a mean age of 29 ± 18 years, 59% (n = 13) were primary, 9% (n = 2) congenital and 32% (n = 7) reactivations. Visual acuity improved from 0.38 ± 0.44 to 0.20 ± 0.27 LogMAR (P = 0.026) after a mean of 37 ± 33 months. Initial lesion size was 2.38 ± 1.1 optic disc areas, reducing to 1.56 ± 1.24 following 2 months (34% reduction, P = 0.028) and to 1.17 ± 0.87 disc areas following one year (51% reduction, P = 0.012). Patients with macula-threatening lesions had worse visual acuity (0.50 ± 0.46 vs. 0.05 ± 0.07 LogMAR, P = 0.047). Primary and reactivation subgroups had similar presentations, visual outcomes and recurrence rates (all P > 0.05). CONCLUSIONS: In this population, primary ocular toxoplasmosis was the most common presentation. Lesion size reduced during the initial months with limited change thereafter and a third of cases recurred. Macula-threatening lesions were associated with worse visual acuity, and no significant differences were seen between the primary and reactivation subgroups.

OPTICAL DENSITY RATIO OF THE SUBRETINAL FLUID IN CHOROIDAL MELANOMA AND METASTASIS.

PURPOSE: To investigate the optical density (OD) characteristics and clinical relevance of subretinal fluid in choroidal melanoma and choroidal metastasis. METHODS: Medical records of patients with choroidal melanoma and choroidal metastasis who underwent optical coherence tomography examinations at diagnosis before any intervention and whose optical coherence tomography scans showed sufficient subretinal fluid for sampling were reviewed. The highest quality B-scan containing subretinal fluid was analyzed. Optical density measurements obtained using ImageJ and optical density ratios (ODRs) were calculated as subretinal fluid OD divided by vitreous OD. Patient details and diagnosis were masked during measurements. Nonparametric tests for independent samples were used to detect differences in ODR between groups. RESULTS: Of the 39 cases of choroidal tumors that met the inclusion criteria, 14 were diagnosed as metastases and 25 as malignant melanoma. There were no significant differences between the groups in age, optical coherence tomography acquisition and parameters of quality, and vitreous OD. Optical density ratio values were significantly lower in metastases cases (mean 0.68, SD ±0.18) than in melanoma cases (0.95 ± 0.33, P = 0.006). Receiver operating characteristic curve analysis yielded an optimal cutoff of ODR = 0.771 (sensitivity = 78.6%, specificity = 72.0%). CONCLUSION: Optical density ratio can serve as an additional test to differentiate between choroidal melanoma and choroidal metastases.

Subretinal Fluid Optical Density and Spectral-Domain Optical Coherence Tomography Characteristics for the Diagnosis of Circumscribed Choroidal Hemangioma.

PURPOSE: To investigate spectral domain-optical coherence tomography (SD-OCT) features of untreated circumscribed choroidal hemangioma (CCH), and the optical density (OD) of the associated subretinal fluid (SRF). PROCEDURES: This international retrospective multicenter study conducted at 5 tertiary retina referral centers included 34 patients with symptomatic CCH imaged on SD-OCT. CCH surface, size, and overlying retinal changes and OD ratio (ODR) were evaluated. RESULTS: The mean ODR of the SRF was 0.808 ± 0.287. Tumor base measured on ultrasound correlated significantly with the ODR (p = 0.012). ODR values in cases of CCH were similar to those of choroidal metastasis, but significantly lower than those of choroidal melanoma (p = 0.006). Thirty-two out of 34 cases (94%) presented with a regular smooth choroidal surface. OCT demonstrated SRF overlying the CCH in 29 eyes (85%). The presence of SRF correlated significantly with a larger basal tumor diameter (p = 0.035). OCT displayed sub- and intraretinal hyperreflective foci, correlating with both larger maximal retinal thickness overlying the tumor (p = 0.031) and the amount of SRF (p = 0.016) in 29 eyes (85%). CONCLUSION: CCH displays typical findings on SD-OCT. ODR is a new important tool in the differential diagnosis of choroidal tumors and should be considered for enhancing the accuracy of diagnosing CCH. This benefit is especially relevant for cases in which the presentation of CCH is atypical.

[UNUSUAL VITREOUS DETACHMENT].

INTRODUCTION: A 49 years old patient with a history of brachytherapy for choroidal melanoma was referred to the ocular emergency room for suspected recurrence due to pigment in the vitreous cavity. On examination, pigmented vitreous secondary to posterior vitreous detachment with traction from the atrophic tumor was observed with no evidence of recurrence.

The Epidemiological, Clinical, and Histopathological Characteristics of Lacrimal Gland Biopsies in a Tertiary Care Center in Israel.

BACKGROUND: The distribution of pathology and clinical characteristics of lacrimal gland diseases are different in different areas of the world. OBJECTIVES: To evaluate the incidence rate, patient characteristics, and indications for surgical intervention of lacrimal gland lesions in a tertiary care center in Israel. METHODS: All biopsied or surgically removed lacrimal gland lesions at the Goldschleger Eye Institute from 2009 to 2015 were identified. The following data were collected: age, gender, indications for surgical intervention, diagnosis, treatment, and prognosis. RESULTS: We evaluated 28 lacrimal gland biopsies from 26 patients (11 men, 15 women). Mean age at biopsy was 47.5 years old. The most common presenting symptoms were: eyelid swollenness (57.14%), ptosis (32.14%), and proptosis (10.71%). All patients underwent computed tomography and magnetic resonance imaging. In 28 cases, infiltrations of the lacrimal gland were found. In nine cases infiltration of muscles or orbital extension were found. The most common pathologies were non-specified inflammation (44.82%), lymphoma (20.68%), and immunoglobulin G4-related disease (10.34%). The treatment was diverse according to the patient diagnosis. Prognosis of lacrimal gland disease was good; however, in five patients the systemic disease progressed. CONCLUSIONS: Lesions of the lacrimal gland comprise a wide variety of pathological findings that require different treatment strategies. Lacrimal gland biopsies enable physicians to precisely recognize the pathology; therefore, it is important to consider this surgical method in any patient with lesions in the lacrimal gland.

[DEVELOPMENT AND CHALLENGES IN TREATMENT OF UVEAL MELANOMA].

INTRODUCTION: Uveal melanoma, the most common primary intraocular malignancy in adults, is potentially a lethal tumour. Since the development of local radiotherapy, tumour control is achieved in the majority of cases and most eyes are salvaged. Despite this, more than 50% of patients develop distant metastatic spread, mainly to the liver, and in the absence of efficient treatments to extend life, die soon after. A great deal of effort has been put into developing prognostic markers for metastatic spread and survival. Novel genetic prognostic tests, recently introduced, are now being clinically used in many ocular oncology centres worldwide. In addition, in most centres, patients are referred for systemic surveillance programs for early detection of liver metastasis. Novel treatment modalities to battle metastatic uveal melanoma are being developed and used in clinical trials. Their efficacy is yet to be proved. This review summarizes the recent developments and current challenges related to uveal melanoma management.

Effects of photoperiod and food on glucose intolerance and subsequent ocular pathology in the fat sand rat.

Type 2 diabetes mellitus (T2DM) and its ocular complications, such as cataract and diabetic retinopathy (DR) have been linked to circadian rhythm-disturbances. Using a unique diurnal animal model, the sand rat (Psammomys obesus) we examined the effect of circadian disruption by short photoperiod acclimation on the development of T2DM and related ocular pathologies. We experimented with 48 male sand rats. Variables were day length (short photoperiod, SP, vs. neutral photoperiod NP) and diet (standard rodent diet vs. low-energy diet). Blood glucose, the presence of cataract and retinal pathology were monitored. Histological slides were examined for lens opacity, retinal cell count and thickness. Animals under SP and fed standard rodent diet (SPSR) for 20 weeks had higher baseline blood glucose levels and lower glucose tolerance compared with animals kept under NP regardless of diet, and under SP with low energy diet (SPLE). Animals under SPSR had less cells in the outer nuclear layer, a lower total number of cells in the retina, and a thickened retina. Higher blood glucose levels correlated with lower number of cells in all cellular layers of the retina and thicker retina. Animals under SPSR had higher occurrence of cataract, and a higher degree of cataract, which correlated with higher blood glucose levels. Sand rats kept under SPSR develop cataract and retinal abnormalities indicative of DR, whereas sand rats kept under NP regardless of diet, or under SPLE, do not. These ocular abnormalities significantly correlate with hyperglycemia.

Orbital Development in Children with Retinoblastoma: An Imaging-Based Study.

PURPOSE: To examine whether children treated for Retinoblastoma (Rb) have impaired orbital development. METHODS: A retrospective case series was performed among children with Rb treated at a single medical center from 2004 to 2020. Orbital volumes and measurements were assessed by 3-dimensional image processing software. The main outcome measures were differences in orbital growth between Rb and non-Rb eyes assessed at last follow-up. RESULTS: Among 44 patients included (mean age 16.09 ± 18.01 months), a positive correlation between age and orbital volume was observed only in the uninvolved, healthy eyes (p = .03). In unilateral cases, orbital growth in the horizontal, vertical, and depth planes was smaller on the affected side compared to the healthy eyes (p < .05). Orbits that underwent enucleation showed decreased growth over time compared to those treated conservatively (p = .017). CONCLUSIONS: Orbital growth rate is slower in the orbits of children treated for Rb compared to healthy orbits. Enucleation negatively affects orbital growth.

Amelanotic conjunctival melanoma in a child.

Purpose: Malignant melanomas of the conjunctiva are extremely rare in children. In this case report we present a conjunctival melanoma of a child. Observations: We report a case of a 7 years old boy who presented with a rapidly growing reddish lesion measuring 8mm in base × 2.5 mm in thickness on the nasal conjunctiva in his right eye. The patient underwent resection of the lesion (with 4 mm margins of the surrounding clinically normal conjunctiva) and cryotherapy to the adjacent conjunctival margins. Histopathology confirmed the diagnosis of conjunctival melanoma. Pathology also can be challenging; a review of pathology is advisable as happened in this case. Systemic workup was negative for metastatic disease. On 73 months of follow up, the patient was stable without local recurrence or secondary systemic disease. Conclusions and Importance: Malignant melanoma can present de novo as an amelanotic rapidly growing conjunctival lesion in children. This case should raise the awareness of the variable clinical presentations, the challenging diagnosis, treatment and follow up of pediatric conjunctival melanoma.

Diffuse choroidal hemangioma in pregnancy: Symptomatic diffuse choroidal hemangioma spontaneously resolving postpartum.

We present the case of a pregnant young woman with symptomatic diffuse choroidal hemangioma (CH), diagnosed with Sturge-Weber syndrome (SWS). Three months postpartum, there was full spontaneous resolution of the subretinal fluid and improvement in the visual acuity (VA). A 29-year-old, 31-week pregnant female with a coagulation disorder and enoxaparin (clexane) treatment, complained of a left visual disturbance of 2 weeks duration. On examination, the right eye was normal; left eye VA was 6/12 (20/40) with a left eyelid port-wine stain and on funduscopic examination there was a serous retinal detachment. On ultrasound, there was diffuse thickening of the choroid with a focus superior and nasal to the disc with active vascularization - a diagnosis of diffuse CH was made. Magnetic resonance imaging (MRI) and MR venography studies of the brain and orbit revealed engorged orbital vasculature, and the diagnosis of SWS was made. Three months after Cesarean section with birth of a healthy baby boy, VA returned to 6/9 with full resorption of subretinal fluid. On fundoscopic exam, there were no retinal or vein occlutions but there were tortuous blood vessels with A-V crossing. This is a rare case of newly diagnosed SWS with symptomatic diffuse CH in pregnancy. Postpartum, there was full resolution of the subretinal fluid. A watchful waiting approach can be considered in such cases.

Herpetic Eye Disease Following the SARS-CoV-2 Vaccinations.

PURPOSE: To describe herpetic ocular infections following SARS-CoV-2 vaccinations. METHODS: A retrospective study of herpetic ocular infections after BNT162b2mRNA vaccination and a literature review. RESULTS: A cohort of five patients: three varicella zoster virus (VZV) and two herpes simplex virus (HSV) cases, as well as 19 literature cases: 9 cases of VZV and 10 cases of HSV post BNT162b2mRNA, AZD1222, mRNA-1273, and CoronaVac vaccinations. All cases presented within 28 days post vaccination. Most VZV and HSV cases (15/19) reported in the literature presented post first vaccine dose, while in our cohort 2 VZV cases presented post second dose and both HSV cases and one VZV case post third dose. The most common presentations were HZO with ocular involvement and HSV keratitis. All eyes had complete resolution; however, one had retinal detachment and three corneal scars. CONCLUSION: Herpetic ocular infections may develop shortly after SARS-CoV-2 vaccinations. Overall, the outcome is good.

Ocular Behçet Disease-Clinical Manifestations, Treatments and Outcomes According to Age at Disease Onset.

Behçet disease (BD) is a multisystemic disease that commonly involves the eyes. Although it affects patients in all age groups, data on ocular disease by age of onset are limited. This retrospective, multicenter study aimed to compare epidemiology, systemic and ocular manifestations, treatments and outcomes between three age groups: juvenile (<18 years), adult (18-39 years) and late (≥40 years) disease onset. The study included 175 ocular BD patients (303 eyes) from Israel and Palestine: juvenile-onset (n = 25, 14.3%), adult-onset (n = 120, 68.6%) and late-onset (n = 30, 17.1%). Most patients in all groups were male. Systemic manifestations were similar in all groups. Systemic co-morbidities were more common in late-onset patients. Bilateral panuveitis was the most common ocular manifestation in all patients. Non-occlusive retinal vasculitis, peripheral vessel occlusions, cataract and elevated intraocular pressure were found more commonly among juvenile-onset eyes. Anterior uveitis and macular ischemia were most common among late-onset eyes, while branch retinal vein occlusion was most common in adult and late-onset eyes. All patients were treated with corticosteroids. Methotrexate, immunomodulatory combinations and biologic treatments were more commonly used for juvenile-onset patients. All groups had a similar visual outcome. Our study showed that patients with ocular BD have varied ocular manifestations and require different treatments according to age of disease onset, but visual outcome is similar.

Retinal vascular occlusions in ocular Behçet disease - a comparative analysis.

PURPOSE: The literature on retinal vascular occlusions in Behçet disease (BD) patients is limited. The aim of this study is to thoroughly investigate retinal vascular occlusions among ocular BD patients. METHODS: Retrospective, multicentre case-control study. Three-hundred and three eyes of 175 patients with ocular BD, from 13 hospitals in Israel and Palestine, were included. Patients were assigned into two groups according to the presence of retinal vascular occlusion. Epidemiology, systemic and ocular manifestations, treatments and outcomes were compared between the groups and risk factors for retinal vascular occlusions were identified. RESULTS: One hundred twenty-five patients (71.4%) were male. The mean age at presentation was 28.2 ± 0.86 years. Retinal vascular occlusions were found in 80 eyes of 54 (30.9%) patients, including branch retinal vein occlusion (51.3%), peripheral vessels occlusions (32.5%), central retinal vein occlusion (13.8%) and arterial occlusions (7.5%). Systemic manifestations were similar among both groups. Anterior uveitis was more common in non-occlusive eyes (p < 0.01). Non-occlusive retinal vasculitis (p = 0.03) and ocular complications were more common in occlusive eyes (p < 0.01). Treatments including mycophenolate mofetil, Infliximab or a combination therapy of anti-metabolite and calcineurin inhibitor were more commonly used by occlusive patients (p < 0.05). Occlusive patients underwent more cataract surgeries (p = 0.03). The occlusive group had worse mean best-corrected visual acuity (BCVA) throughout follow-up (p < 0.01). Risk factors for retinal vascular occlusions included male sex and Jewish ethnicity (p < 0.05). CONCLUSION: Retinal vascular occlusions were found in a third of ocular BD patients. Occlusive eyes had a worse prognosis. Risk factors for vascular occlusions were identified.