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Rabih Hage,1 Claire Alapetite,2 Hervé Brisse,3,4 Kevin Zuber,5 Augustin Lecler,6 Guillaume Lot,7 Caroline Le Guerinel,7 Catherine Vignal-Clermont,1 Herve Boissonnet7 1Neuro-ophthalmology Department, Hôpital Fondation A. de Rothschild, Paris, France; 2Radiation Oncology Department, and Proton Center Institut Curie, Paris-Orsay, France; 3Imaging Department, Institut Curie, Paris, France; 4Université des Sciences et Lettres, Paris, France; 5Department of Statistics and Clinical Research, Hôpital Fondation A. de Rothschild, Paris, France; 6Radiology Department, Hôpital Fondation A. de Rothschild, Paris, France; 7Neurosurgery Department, Hôpital Fondation A. de Rothschild, Paris, FranceCorrespondence: Rabih Hage Tel/Fax +33148036322Email rhage@for.parisPurpose: Management of optic nerve sheath meningiomas (ONSM) remains challenging. Photon radiation therapy (PhRT) is the most common treatment for sight-threatening ONSM. Proton beam therapy (PBT) is less commonly used because it is more expensive and because there are questions about its efficacy specifically in relation to ONSM. PBT has the theoretical advantage of reducing radiation exposure to adjacent structures. We report the visual outcome of patients with primary ONSM managed at the Fondation Ophtalmologique Adolphe de Rothschild, Paris, France, and treated with PBT at the Centre de Protonthérapie, Institut Curie, Orsay, France.Methods: We conducted a retrospective review of all patients with primary ONSM who received PBT (either by itself or following surgery) between January 2006 and January 2019. Neuro-ophthalmic examinations were performed at presentation and after radiotherapy, and, when applicable, after surgery. Meningiomas were measured at the time of diagnosis and at each follow-up MRI examination.Results: Sixty patients (50 women, 10 men; mean age, 45.2± 11.1y) were included, of whom 29 underwent surgery. At presentation, 52 (87%) of them had decreased vision (average visual acuity: 0.6 logMAR). Fundus examination showed optic disc swelling (n=27; 46.5%), optic disc pallor (n=22; 37.9%), optic disc cupping (n=2; 3.4%), opto-ciliary shunt (n=8; 13.8%), or choroidal folds (n=5; 8.6%). Otherwise, it was unremarkable (n=7; 12.1%). After treatment, visual function was stable overall. Fundus examination showed pallor (n=47; 83.9%), swelling (n=3; 5.4%), or cupping (n=2; 3.4%) of the optic disc, or was unremarkable (n=5; 8.9%). The visual field of 8 patients worsened, while 3 developed asymptomatic retinal hemorrhages. Tumor shrunk significantly in 8 patients at 1 year after PBT and remained stable in size in all others. Patients with opto-ciliary shunts had significantly worse visual outcome than other patients. Retinal abnormalities were observed in 11 patients during follow-up.Conclusion: PBT alone or in association with surgery appears to be a safe and efficient treatment for ONSM, reducing the tumor size and stabilizing visual function. The risk of developing radiation retinopathy seems to be higher when patients had upfront surgery.Keywords: optic nerve sheath meningioma, ONSM, proton beam therapy, PBT, compressive optic neuropathy, brain tumor, visual loss, opto-ciliary shunt, radiation retinopathy, RON

Objective REFLECT is the first randomised, double-masked, placebo-controlled multicentre phase 3 clinical trial that evaluated the efficacy and safety of bilateral intravitreal (IVT) injection of lenadogene nolparvovec in subjects with Leber hereditary optic neuropathy carrying the m.11778G>A mutation.Methods and analysis A total of 98 subjects were enrolled with vision loss of ≤12 months. The subjects were randomised to one of two treatment arms with all subjects receiving an intravitreal (IVT) injection of lenadogene nolparvovec in their first affected eye and the second-affected eye randomised to receive IVT of either lenadogene nolparvovec or placebo.Results The majority of subjects were male with a mean duration of vision loss of 8.3 months. All but one subject experienced bilateral loss of vision at the time of injection. The mean best-corrected visual acuity of first-affected eyes was worse compared with second/not-yet-affected eyes. Analysis of retinal anatomical parameters showed increased thinning in the first-affected eyes when compared with the second/not-yet-affected eyes with both treatment arms showing significant changes compared with unaffected individuals.Conclusion The REFLECT trial is the third and the largest phase 3 clinical study evaluating lenadogene nolparvovec in m.11778G>A Leber hereditary optic neuropathy (LHON) subjects. The observed demographics in REFLECT are consistent with previous reports in LHON subjects in the acute and dynamic phases of LHON disease. Combined with the visual function and anatomical parameters obtained in the previous RESCUE and REVERSE trials, REFLECT has provided a uniformly collected data set that should help direct future LHON clinical trials.