Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper.

Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non small-cell lung cancers. Therefore, their use will not be limited anymore to selected hospitals involved in clinical trials. Indeed, they will be routinely prescribed in many cancer centers across the world. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events (irAEs). This new family of dysimmune toxicities remains largely unknown to the broad oncology community. Although severe irAEs remain rare (∼10% of cases under monotherapy), they can become life-threatening if not anticipated and managed appropriately. Over the last 5 years, Gustave Roussy has accumulated a significant experience in the prescription of immune checkpoint blockade (ICB) antibodies and the management of their toxicities. Together with the collaboration of Gustave Roussy's network of organ specialists with expertise in irAEs, we propose here some practical guidelines for the oncologist to help in the clinical care of patients under ICB immunotherapy.

[Viral and chlamydial conjunctivitis]. / Conjonctivites virales et chlamydiennes.

Viral conjunctivitis is the most common type of conjunctivitis. It is contagious and is predominantly seen as adenovirus-related conjunctivitis and keratoconjunctivitis (ADV). These infections are the most frequent ocular surface infections and can lead to conjunctival scarring and corneal opacities. Other types of viral conjunctivitis are often secondary to systemic infection and typically resolve spontaneously. Chlamydial conjunctivitis, on the other hand, is dominated by trachoma, which remains endemic in 42 countries and is still the leading cause of infectious blindness worldwide. In industrialized countries, chlamydia can also cause neonatal conjunctivitis and sometimes chronic conjunctivitis, occasionally associated with sexually transmitted diseases. This comprehensive review provides clinicians with essential microbiological, epidemiological, clinical, and therapeutic data on these two major groups of infectious conjunctivitis.

[Micropulsed diode laser transscleral cyclophotocoagulation: An effective technique whose role remains to be defined]. / Cycloaffaiblisement au laser diode micropulsé : une technique efficace, mais dont la stratégie reste à définir.

Micropulse Transscleral Cyclophotocoagulation (MP-TSCP) is a recently developed cyclodestructive procedure less aggressive than conventional TSCP. In this study, we aimed to evaluate the safety and efficacy of MP-TSCP in a real-life setting. MATERIAL AND METHODS: We retrospectively included all MP-TSCP cases performed in the Bicêtre Hospital Ophthalmology department between January 2017 and September 2019. Intraocular pressure (IOP) and hypotensive medications were recorded preoperatively, at month 1, 3, 6 and at the conclusion of follow-up, as well as postoperative adverse events. Success was defined as an IOP between 6 and 21mmHg with a decrease of at least one medication or an IOP reduction>20%. RESULTS: Thirty eyes (28 patients) were included. Preoperative IOP was 27.2±10.6mmHg, with 3.5±0.6 hypotensive medications, the mean deviation on the Humphrey 24-2 visual field was -21.9±6.9dB, and 43% of eyes had a past history of filtering surgery. The mean follow-up was 13.5±8.1 months. Eleven patients (37%) had to be retreated with MP-TSCP during follow-up. At 3 and 6 months and at the conclusion of follow-up, the IOP was 18.3±7.3mmHg (-33%; P<0.0001), 22.5±11.8mmHg, (-17%; P=0.052), 22.7±12.0mmHg (-16,5%; P<0.050), respectively. The success rates were 57%, 50% et 53% at 3 months, 6 months and at the conclusion of follow-up, respectively. Severe adverse events included 3 cases of corneal ulcers and 2 cases of severe but transient ocular hypotony without visual impairment. CONCLUSION: MP-TSCP is an effective procedure for severe and/or refractory glaucoma, but retreatments are required in more than one-third of cases. Further studies are warranted to define factors predictive of success and indications for retreatment.

[Ocular manifestations of viral diseases]. / Atteintes ophtalmologiques des infections virales.

Viral infections may involve all ocular tissues and may have short and long-term sight-threatening consequences. Among them, ocular infections caused by herpesviruses are the most frequent. HSV-1 keratitis and kerato-uveitis affect approximately are the leading cause of infectious blindness in the Western world, mainly because of corneal opacification caused by recurrences. For this reason, they may warrant long-term antiviral prophylaxis. Herpes zoster ophthalmicus, accounts for 10 to 20% of all shingles locations and can be associated with severe ocular involvement (keratitis, kerato-uveitis) of which a quarter becomes chronic/recurrent. Post herpetic neuralgias in the trigeminal territory can be particularly debilitating. Necrotizing retinitis caused by herpesviruses (HSV, VZV, CMV) are seldom, but must be considered as absolute visual emergencies, requiring urgent intravenous and intravitreal antiviral treatment. Clinical pictures depend on the immune status of the host. Adenovirus are the most frequent cause of infectious conjunctivitis. These most often benign infections are highly contagious and may be complicated by visually disabling corneal lesions that may last over months or years. Some arboviruses may be associated with inflammatory ocular manifestations. Among them, congenital Zika infections may cause macular or optic atrophy. Conjunctivitis is frequent during the acute phase of Ebola virus disease. Up to 15% of survivors present with severe chronic inflammatory ocular conditions caused by viral persistence in uveal tissues. Finally, COVID-19-associated conjunctivitis can precede systemic disease, or even be the unique manifestation of the disease. Utmost caution must be taken because of viral shedding in tears.

[Multimodal evaluation of the ocular surface using a the new Lacrydiag device]. / Place du NIBUT automatisé dans l'évaluation multimodale de la surface oculaire dans le syndrome sec avec le Lacrydiag.

INTRODUCTION: Dry eye disease is a very frequent condition with a significant impact on patients' quality of life. The most common clinical sign is fluorescein break up time (BUT). Recently, non-invasive measurement of BUT (NIBUT) by Placido disc analysis has been proposed to replace FBUT. We performed an automated NIBUT analysis using Lacrydiag and compared the values obtained with other typical dry eye criteria. METHODS AND MATERIALS: A retrospective study was carried out in the Bicêtre ophthalmology department from July 1 through October 30. Dry eye patients over 18 years of age with Oxford scores>1 and OSDI scores>22 were included. They underwent slit lamp examination to determine fluorescein BUT, Oxford and Arita MGD scores. On the same day, they were tested with the Lacrydiag to assess NIBUT, tear lake height and meibography. OSDI and Schirmer's testing were performed on the date of examination. In this study, only patients' right eyes were included. The correlation between NIBUT and OSDI, Schirmer's testing and tear lake height was analyzed by Pearson's test. The correlation between NIBUT and fluorescein BUT was analysed by both Pearson and Bland-Altman statistical tests. RESULTS: Thirty right eyes (21 women, 9 men) were included. The mean age was 62.3 years (SD 16.0), mean OSDI 49.4 (SD=20.1), mean Oxford score 3.33 (SD 2.1), mean NIBUT 6.91sec (SD 3.4), and mean FBUT 3.6sec (SD 1.8). The NIBUT and FBUT were significantly correlated (R=0.139; P=0.042), with an even more significant concordance (r=0.55; P=0.001) on Bland-Altman graphic analysis, but the mean NIBUT was 2.7 seconds higher than the FBUT (P=0.001 on Bland-Altman analysis). In addition, NIBUT was correlated with the Oxford score (R=0.156; P=0.031), but not with Schirmer I score (R=0.120; P=0.061), OSDI score (R=0.018; P=0.48), tear lake height (R=0.04; P=0.148), or Arita meibomian gland dysfunction score (R=0; P=0.933). CONCLUSION: NIBUT is a possible alternative to FBUT for the measurement of tear film stability, with the advantage of lack of dependence on the amount of fluorescein instilled. In addition, modern imaging methods allow for automated, and thus reproducible, measurement. However, its role in the diagnostic tool kit remains to be precisely defined, especially given its weak correlation with other markers of dry eye and its significant difference from FBUT. The definitive diagnosis of dry eye thus remains based on the combined analysis of signs and symptoms.

Punctal and canalicular plugs: Indications, efficacy and safety.

Lacrimal occlusion with punctal or canalicular plugs have been used to treat dry eye disease for more than 40 years. Indeed, punctal plugs constitute a safe and effective tool to retain the natural tear film and prolong the effect of tear substitutes. A wide variety of plugs is available, differing in their design, location (punctal versus canalicular) and their resorbability. There indications have increasingly broadened, and they are now one of the treatment options for numerous ocular surface diseases. Current research focuses on using punctal plugs for extended delivery of drugs to the ocular surface. This review addresses physiology of lacrimal drainage, available models of punctal plugs, their indications, practical details of prescribing and placing punctal and canalicular plugs, and possible complications.

[Punctal and canalicular plugs: Indications, efficacy and safety (French translation of the article)]. / Les bouchons lacrymaux : indications, efficacité et tolérance.

Lacrimal occlusion with punctal or canalicular plugs have been used to treat dry eye disease for more than 40 years. Indeed, punctal plugs constitute a safe and effective tool to retain the natural tear film and prolong the effect of tear substitutes. A wide variety of plugs is available, differing in their design, location (punctal versus canalicular) and their resorbability. There indications have increasingly broadened, and they are now one of the treatment options for numerous ocular surface diseases. Current research focuses on using punctal plugs for extended delivery of drugs to the ocular surface. This review addresses physiology of lacrimal drainage, available models of punctal plugs, their indications, practical details of prescribing and placing punctal and canalicular plugs, and possible complications.

[Bilateral uveitis associated with nivolumab therapy]. / Uvéite bilatérale associée à un traitement par nivolumab.

Immune-related adverse events (IRAEs) are rare but serious adverse events that may be associated with inhibitors of few immune control points. The purpose here is to report the case of an inflammatory ocular disease, potentially linked to the immunity and use of nivolumab, a new immunological agent used for the treatment of a solid tumor. In spite of the involvement of this treatment in the onset of inflammation, we must always seek another cause. It is possible to continue this treatment by considering the benefit/risk balance for each patient. Close collaboration between oncologists and ophthalmologists is necessary in the diagnosis and rapid management of these IRAE ocular related to these new emerging therapies.

Bilateral uveitis associated with nivolumab therapy.

New anticancer therapies, immune pathway inhibitors, may cause immune-related adverse events (IRAE). Immune-related ocular toxicities are rare but are potentially serious adverse events. The purpose of this article is to report a case of ocular inflammatory involvement potentially related to the immune response and the use of nivolumab, a new immunologic agent used for the treatment of a solid tumor. Despite the implication of this therapy in the occurrence of inflammation, other causes must always be ruled out. It is possible to continue this therapy in consideration of the risk/benefit ratio for each patient. Close collaboration between oncologists and ophthalmologists is necessary in the diagnosis and timely management of IRAE related to these new emerging therapies.

[Variability of chloroquine and hydroxychloroquine retinopathy among various ethnicities]. / Différences ethniques parmi les patients souffrant de toxicité maculaire aux antipaludéens de synthèse.

INTRODUCTION: Current screening recommendations for chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy are based on central 10°C static perimetry and a high-resolution SD-OCT with a special attention to the inferior part of the macula where the toxicity usually starts by ellipsoid zone disruption. However, Melles and Marmor, have recently shown a great variability in the topography of the initial toxicity observed among various ethnicities, which is important to keep in mind so as not to miss early toxicity in certain subgroups of patients. METHODS: Review of the literature. RESULTS: Ethnic differences have been shown regarding the topography of the initial retinal toxicity of CQ and HCQ, particularly between Caucasian and Asian subjects. In Caucasians, the first signs of toxicity are more often localized in the inferior para-foveal area associated with a decrease in retinal sensitivity in the upper 10°C visual field. However, in Asian subjects, the first signs of toxicity appear more pericentral (still inferior) with an extramacular pattern that could be missed by the usual 10°C visual field screening. DISCUSSION/CONCLUSION: The pathophysiology of these ethnic differences is unknown and may be due to distinct genetic predisposition to CQ and HCQ toxicity. Screening strategies should be adjusted to the ethnicity and performed in Asian subjects with larger visual fields (30°C), along with SD-OCT, looking for ellipsoid disruption≥8°C from the fovea. The recognition of this pericentral topography and an adjusted screening protocol should avoid late diagnosis in Asians treated with CQ and HCQ.

[Ocular surface aging: Pathophysiology and consequences for management]. / Vieillissement de la surface oculaire : physiopathologie et conséquences pratiques pour la prise en charge.

All the components of the ocular surface and the lacrimal system are affected by aging. Aging induces lacrimal gland fibrosis, Meibomian gland dysfunction, loss of corneal sensitivity, decreased corneal cell density, impairment of immune defences, increased local inflammation associated with hormonal changes, conjunctivochalasis, lid abnormalities, etc. Furthermore, homeostasis of the ocular surface may be altered by various age-related systemic comorbidities and iatrogenic interventions. Altogether, aging is considered the most predominant risk factor for dry eye disease. The increasing knowledge of the pathophysiology of aging of the ocular surface allows for refinement of the management of ocular surface disease in the elderly.

[Update on recommendations for screening for hydroxychloroquine retinopathy]. / Mise à jour des recommandations sur la toxicité rétinienne des antipaludéens de synthèse.

INTRODUCTION: Recommendations for screening for chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy have recently been changed by the American Academy of Ophthalmology, taking into account new published data on toxicity prevalence, risk factors, location of onset in the retina and the efficacy of screening tests. METHODS: Literature review. RESULTS AND DISCUSSION: The risk of developing CQ or HCQ retinopathy depends on the daily dose and duration of treatment. At recommended doses, the risk is<1 % at 5 years, <2 % at 10years but increases to about 20 % after 20years of treatment. The maximum recommended daily dose is 5.0mg/kg for HCQ and 2.3mg/kg for CQ. The two main risk factors are the daily dose and duration of treatment. The presence of kidney failure and treatment with tamoxifen are also significant risk factors. A baseline examination should be performed at the initiation of treatment to rule out pre-existing maculopathy. The screening is then annual and starts from the 5th year of treatment. The two tests recommended for screening are the automated visual field and spectral domain OCT. Multifocal ERG and autofluorescence fundus imaging are only carried out secondarily to confirm the pathology.

Fundus autofluorescence in retinal artery occlusion: A more precise diagnosis.

IMPORTANCE: Retinal artery occlusion (RAO) is a medical emergency associated with a high risk of cerebral vascular accident and other cardiovascular events. Among patients with non-arteritic RAO, a retinal embolus is observed in approximately 40% of cases. Fundus examination and retinography are not reliable to predict the nature of the emboli. OBSERVATIONS: We report three consecutive cases of central and branch RAO that were investigated with fundus autofluorescence, fluorescein angiography and color retinal photographs. All patients underwent complete neurological and cardiovascular workups, with brain imaging, cardiac Doppler ultrasound, carotid Dopplers and Holter ECG's, to determine the underlying mechanism of retinal embolism. In the three cases, aged 77.7±4 years (2 women and 1 man), fundus autofluorescence demonstrated hyperautofluorescent emboli. In two cases, it allowed visualization of emboli that were not detected with fundus examination or retinography. The cardiovascular work-up demonstrated atheromatous carotid or aortic plaques in all patients. In one case, it permitted the diagnosis of RAO. Two of the three cases were considered to be of atherosclerotic origin and one of undefined origin. CONCLUSION AND RELEVANCE: Fundus autofluorescence may help to detect and characterize retinal emboli. Since lipofuscin, which is present in large quantity in atherosclerotic plaques, is the main fluorophore detected with fundus autofluorescence, this non-invasive and simple examination may give information about the underlying mechanism of retinal embolism, and thus impact the etiologic assessment of RAO. Additional studies are necessary to confirm this potential role of autofluorescence.

Accumulation of mitochondrial DNA deletions in human retina during aging.

PURPOSE: The authors investigated the presence of mitochondrial DNA (mtDNA) mutations in aging human retina. METHODS: A quantitative polymerase chain reaction technique for studying the common mtDNA 4977-deletion (delta mtDNA4977) in retinal pigment epithelium (RPE) and neural retinal (NR) was developed. RESULTS: Although no deletion was detected in the fetus, every adult RPE and NR had this common deletion. The ratio of the deleted delta mtDNA4977 to the total mtDNA increased significantly in elderly persons 60 to 110 years of age and was greater in peripheral than in central RPE. CONCLUSIONS: These results suggest that at least one type of mutation accumulates in the mtDNA in the retina during aging, reflecting a general phenomenon of genomic instability that could influence its function.

[Dragged disk syndrome. Review of etiologies. Apropos of a case]. / Syndrome d'attraction papillaire. Revue des etiologies. A propos d'un cas.

A young woman presented with an elevated, retinal yellow-white lesion in mid-periphery of one eye, associated with a dragged disc. Different aetiologies were discussed including retinopathy of prematurity, familial exudative vitreoretinopathy, congenital retinal folds, incontinentia pigmenti, Eales' disease, toxocariasis, combined hamartoma of the retina and the pigment epithelium.

[Surgical treatment of post-traumatic macular holes]. / Traitement chirurgical des trous maculaires post-traumatiques.

BACKGROUND: Macular hole is a rare complication of blunt ocular trauma. Little is known about its spontaneous course and only a few operated cases have been reported. METHOD: We present five cases of post-traumatic macular holes, 4 of which have been operated on. RESULTS: In one case, the hole sealed spontaneously due to the formation of a slightly contractile epimacular membrane, and visual acuity improved from 0.1 to 0.5. The other four cases underwent vitrectomy, posterior hyaloid stripping, fluid-gas exchange and 12 days of postoperative positioning. In addition, two of these cases had autologous platelet injection. The macular hole closed in 3 of the 4 cases and vision improved in two. CONCLUSION: Traumatic macular holes can close spontaneously, although this is rare. Usually, surgery with or without healing adjuvants is needed to close the hole. Visual results may be good if there is no damage to the subfoveal retinal pigment epithelium or to Bruch's membrane.