Thibaud Mathis

Activated monocytes resist elimination by retinal pigment epithelium and downregulate their OTX2 expression via TNF‐α

Orthodenticle homeobox 2 (OTX2) controls essential, homeostatic retinal pigment epithelial (RPE) genes in the adult. Using cocultures of human CD14+ blood monocytes (Mos) and primary porcine RPE cells and a fully humanized system using human‐induced pluripotent stem cell‐derived RPE cells, we show that activated Mos markedly inhibit RPEOTX2 expression and resist elimination in contact with the immunosuppressive RPE. Mechanistically, we demonstrate that TNF‐α, secreted from activated Mos, mediates the downregulation of OTX2 and essential RPE genes of the visual cycle among others. Our data show how subretinal, chronic inflammation and in particular TNF‐α can affect RPE function, which might contribute to the visual dysfunctions in diseases such as age‐related macular degeneration (AMD) where subretinal macrophages are observed. Our findings provide important mechanistic insights into the regulation of OTX2 under inflammatory conditions. Therapeutic restoration of OTX2 expression might help revive RPE and visual function in retinal diseases such as AMD.

Mechanisms of phosphenes in irradiated patients

Anomalous visual perceptions have been reported in various diseases of the retina and visual pathways or can be experienced under specific conditions in healthy individuals. Phosphenes are perceptions of light in the absence of ambient light, occurring independently of the physiological and classical photonic stimulation of the retina. They are a frequent symptom in patients irradiated in the region of the central nervous system (CNS), head and neck and the eyes. Phosphenes have historically been attributed to complex physical phenomena such as Cherenkov radiation. While phosphenes are related to Cherenkov radiation under high energy photon/electron irradiation conditions, physical phenomena are unlikely to be responsible for light flashes at energies used for ocular proton therapy. Phosphenes may involve a direct role for ocular photoreceptors and possible interactions between cones and rods. Other mechanisms involving the retinal ganglion cells or ultraweak biophoton emission and rhodopsin bleaching after exposure to free radicals are also likely to be involved. Despite their frequency as shown in our preliminary observations, phosphenes have been underreported probably because their mechanism and impact are poorly understood. Recently, phosphenes have been used to restore the vision and whether they might predict vision loss after therapeutic irradiation is a current field of investigation. We have reviewed and also investigated here the mechanisms related to the occurrence of phosphenes in irradiated patients and especially in patients irradiated by proton therapy for ocular tumors.Anomalous visual perceptions have been reported in various diseases of the retina and visual pathways or can be experienced under specific conditions in healthy individuals. Phosphenes are perceptions of light in the absence of ambient light, occurring independently of the physiological and classical photonic stimulation of the retina. They are a frequent symptom in patients irradiated in the region of the central nervous system (CNS), head and neck and the eyes. Phosphenes have historically been attributed to complex physical phenomena such as Cherenkov radiation. While phosphenes are related to Cherenkov radiation under high energy photon/electron irradiation conditions, physical phenomena are unlikely to be responsible for light flashes at energies used for ocular proton therapy. Phosphenes may involve a direct role for ocular photoreceptors and possible interactions between cones and rods. Other mechanisms involving the retinal ganglion cells or ultraweak biophoton emission and rhodopsin bleaching after exposure to free radicals are also likely to be involved. Despite their frequency as shown in our preliminary observations, phosphenes have been underreported probably because their mechanism and impact are poorly understood. Recently, phosphenes have been used to restore the vision and whether they might predict vision loss after therapeutic irradiation is a current field of investigation. We have reviewed and also investigated here the mechanisms related to the occurrence of phosphenes in irradiated patients and especially in patients irradiated by proton therapy for ocular tumors.

In response to: Parodi MB, Iacono P, Zucchiatti et al. Choroidal Neovascularization Associated with Multiple Evanescent White Dot Syndrome Treated with Intravitreal Ranibizumab

Abstract In response to the article by Parodi et al. about choroidal neovascularization (CNV) associated with Multiple Evanescent White Dot Syndrome (MEWDS) treated with intravitreal Ranibizumab. This article highlights the efficacy of intravitreal Ranibizumab in the treatment of CNV associated with MEWDS. In our experience, CNV is mostly associated with MEWDS in cases of a wider inflammatory spectrum such as overlapping syndrome with multifocal choroiditis (MFC) or punctuate inner choroidopathy (PIC). The whole pattern of the case presented in the article is compatible with the diagnosis of PIC, meaning that this case described an overlapping between MEWDS and PIC diagnoses. Although the authors wrote that CNV is secondary to MEWDS, another possible hypothesis is that CNV is secondary to PIC. Thus, MEWDS could be secondary to PIC and/or CNV.

Multimodal imaging findings in ‘hyper-early’ stage MEWDS

Objective To describe a new stage of multiple evanescent white dot syndrome (MEWDS), occurring at a very early phase of the disease. Methods Retrospective analysis of clinical, angiographic and tomographic findings in four patients with ‘hyper-early’ stage MEWDS. Results In four patients seen within 1 week of the onset of symptoms, fundus analysis revealed macular granity and the classic yellow–white dots, some having no corresponding hyperautofluorescent pattern. Spectral-domain optical coherence tomography (SD-OCT) showed central foveal disruption of the ellipsoid zone (EZ) and interdigitation layer with a hyper-reflective dome-shaped lesion. In two patients, fluorescein angiography (FA) revealed an intermediate hypofluorescent perimacular halo, whereas late indocyanine green angiography (ICGA) showed a hyperfluorescent halo as well as the classic MEWDS features. After a few days, the EZ disruption appeared complete on OCT and fundus autofluorescence (FAF) in all patients. Visual acuity, OCT and FAF findings had fully recovered within 3 months. Conclusions We have shown a new feature of MEWDS on FAF, OCT, FA and ICGA, corresponding to a very early stage of the disease.

Polypoidal Choroidal Vasculopathy Occurring in the Context of Large Colloid Drusen

The authors report, for the first time, an association between large colloid drusen (LCD) and choroidal neovascularization in a 58-year-old man. Multimodal imaging confirmed the diagnosis of LCD in both eyes and polypoidal choroidal vasculopathy in the left eye. The patient was treated with monthly intravitreal injections of aflibercept (Eylea; Regeneron, Tarrytown, NY). The authors hypothesize that these deposits are probably associated with retinal pigment epithelium dysfunction and could thus lead to delayed neovascularization and atrophy. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1154-1156.].

New concepts in the diagnosis and management of choroidal metastases

ABSTRACT The most frequent site of ocular metastasis is the choroid. The occurrence of choroidal metastases has increased steadily due to the longer survival of metastatic patients and the improvement of diagnostic tools. Fundoscopy, ultrasonography, and fluorescein angiography are now complemented by indocyanine green angiography and optical coherence tomography. Choroidal tumor biopsy may also confirm the metastatic nature of the tumor and help to determine the site of the primary malignancy. There is currently no consensus on the treatment strategy. Most patients have a limited life expectancy and for these complex treatments are generally not recommended. However, recent advances in systemic therapy have significantly improved survival of certain patients who may benefit from an aggressive ocular approach that could preserve vision. Although external beam radiation therapy is the most widely used treatment, more advanced forms of radiotherapy that are associated with fewer side effects can be proposed in select cases. In patients with a shorter life expectancy, systemic therapies such as those targeting oncogenic drivers, or immunotherapy can induce a regression of the choroidal metastases, and may be sufficient to temporarily decrease visual symptoms. However, they often acquire resistance to systemic treatment and ocular relapse usually requires radiotherapy for durable control. Less invasive office‐based treatments, such as photodynamic therapy and intravitreal injection of anti‐VEGF, may also help to preserve vision while reducing time spent in medical settings for patients in palliative care. The aim of this review is to summarize the current knowledge on choroidal metastases, with emphasis on the most recent findings in epidemiology, pathogenesis, diagnosis and treatment. HighlightsChoroid is the most common ocular site for metastatic spread, especially for breast and lung cancer.Enhanced imaging of the choroid allows better understanding and precise diagnosis of choroidal metastases.In case the primary remains unknown, tumor biopsy may help identify the primary and guide treatment.To date, fractionated radiotherapy remains the treatment of choice for choroidal metastases.The place of systemic targeted therapy and “office‐based” treatment such as PDT or intravitreal antiVEGF should be considered.

Re: Zarubina et al.: Prevalence of subretinal drusenoid deposits in older persons with and without age-related macular degeneration, by multimodal imaging (Ophthalmology 2016;123:1090-1100)

patients, and consumption of alcohol or caffeinated/noncaffeinated beverages before OCT measurements. We also wonder whether the body mass indices of the patients were taken into consideration, and the results of their systemic blood pressure measurements because these parameters significantly affect CT. We recommend that local, systemic, and environmental parameters be considered when OCT measurements are taken and that the measurements be obtained at consistent times between days.

Cataract Avoidance With Proton Therapy in Ocular Melanomas

Purpose The lens is a radiosensitive organ. Any dose of cephalic irradiation can give rise to radiation-induced cataracts. Contrary to other forms of radiotherapy, proton therapy (PT) can spare all or part of the lens due to accurate dose deposition. We investigated whether a lens-sparing approach was relevant to avoid cataracts in uveal melanoma patients. Methods Patients were referred for PT from onco-ophthalmologists of private and academic institutions. Patients without preexisting cataracts or implants were entered in a prospective database. Dose thresholds responsible for cataracts were investigated in volumes of lens or lens periphery. Lens opacifications and de novo vision-impairing cataracts (VICs) had biannual follow up by ophthalmologists blinded to lens dose. Correlations between dose-volume relationships and VICs were assessed using univariate/multivariate regressions. Results Between 1991 and 2015, 1696 uveal melanoma patients were consecutively treated with PT. After a median follow up of 48 months, 14.4% and 8.7% of patients had cataracts and VIC within median times of 19 and 28 months, respectively. Median values of mean lens and lens periphery doses were 1.1 (radiobiologically effective [RBE] dose in photon-equivalent grays [GyRBE]) and 6.5 GyRBE, respectively. The lens received no dose in 25% of the patients. At an irradiated lens volume of ≤5%, there was no significantly increased risk for VIC below a dose of 10 GyRBE. Conclusions A lens-sparing approach is feasible and results not only in reduced need for cataract surgery but also in better fundus-based tumor control. Reassessment of radioprotection rules for lens dose thresholds may follow.