Radiprodil, a selective GluN2B negative allosteric modulator, rescues audiogenic seizures in mice carrying the GluN2A(N615S) mutation.

BACKGROUND AND PURPOSE: GRIN-related disorders are neurodevelopmental disorders caused by mutations in N-methyl-D-aspartate receptor (NMDAR) subunit genes. A large fraction of these mutations lead to a 'gain of function' (GoF) of the NMDAR. Patients present with a range of symptoms including epilepsy, intellectual disability, behavioural and motor. Controlling seizures is a significant unmet medical need in most patients with GRIN-related disorders. Although several hundred GRIN mutations have been identified in humans, until recently none of the mouse models carrying Grin mutations/deletions showed an epileptic phenotype. The two recent exceptions both carry mutations of GluN2A. The aim of this study was to assess the efficacy of radiprodil, a selective negative allosteric modulator of GluN2B-containing NMDARs, in counteracting audiogenic seizures (AGS) in a murine model carrying the GluN2A(N615S) homozygous mutation (Grin2aS/S mice). EXPERIMENTAL APPROACH: Grin2aS/S mice were acutely treated with radiprodil at different doses before the presentation of a high-frequency acoustic stimulus commonly used for AGS induction. KEY RESULTS: Radiprodil significantly and dose-dependently reduced the onset and severity of AGS in Grin2aS/S mice. Surprisingly, the results revealed a sex-dependent difference in AGS susceptibility and in the dose-dependent protection of radiprodil in the two genders. Specifically, radiprodil was more effective in female versus male mice. CONCLUSION AND IMPLICATIONS: Overall, our data clearly show that radiprodil, a GluN2B selective negative allosteric modulator, may have the potential to control seizures in patients with GRIN2A GoF mutations. Further studies are warranted to better understand the sex-dependent effects observed in this study.

Reproducibility of SIMPLE classification for diabetic retinopathy screening and its comparison to current Italian guidelines.

PURPOSE: To evaluate the reproducibility of SIMPLE (Single field Image Multi Parameters defined Lesions Extent), a new Diabetic Retinopathy (DR) classification for screening of 45° single field fundus pictures of patients with diabetes (PwDM), assessing DR, Diabetic Maculopathy (DMac) and referral rate agreement and comparing it to current Italian Guidelines (IG). MATERIALS AND METHODS: We conducted a retrospective, observational, multicentre study, collecting 1000 retinal 45° single field images of PwDM obtained during routine visits in two diabetes clinics. Three ophthalmologists evaluated each image, determining the presence and number of specific DR lesions and then assigning a stage according to the current IG for screening. SIMPLE staging was performed automatically via Excel software, based on the pre-specified DR characteristics observed by the graders. We analysed intra-centre, inter-centre and total inter-grader agreement for DR and DMac stage and referral rate of the two classifications. RESULTS: Agreement amongst the three graders was consistently higher when using SIMPLE classification than when using current IG classification. For DR, kappa (k) was 0.86 with IG and 0.95 with SIMPLE classification; for DMac, k-IG was 0.78, while k-SIMPLE was 0.96; concordance on the referral rate was 0.91 with IG and 0.99 with SIMPLE. Similar results were obtained in sub-analyses for the evaluation of intra-centre and inter-centre concordance. CONCLUSIONS: Our results suggest that the new SIMPLE classification has an excellent reproducibility amongst graders, comparable or superior to the current IG for DR screening proposed in 2015, improving the standardisation of the decision on referability.

Enhancing Intermediate Vision in Patients Affected by Epiretinal Membrane Treated by Phaco-Vitrectomy.

BACKGROUND: The aim of this research was to see if a refractive enhanced monofocal IOL (Eyhance IOL, IOL Abbott Medical Optics, Inc., Santa Ana, CA, USA) can provide better intermediate vision in patients undergoing phaco-vitrectomy due to cataract and epiretinal macular membrane (ERM). METHODS: A nonrandomized prospective observational comparative study enrolled patients affected by cataract and ERM undergoing phaco-vitrectomy. A follow up of 6 months was established. Corrected and uncorrected visual acuity of both monocular and binocular types were assessed regarding intermediate and far distances. The CATQUEST 9-SF questionnaire was administered preoperatively and at the last follow-up. RESULTS: Twenty-three eyes of twenty-three patients were enrolled, with 11 in the enhanced monofocal group. The uncorrected and corrected distance visual acuity after 6 months was not statistically different. Both monocular and binocular uncorrected intermediate visual acuity after 6 months were higher in the enhanced monofocal group (p < 0.001). The corrected intermediate visual acuity after 6 months was higher in the enhanced monofocal group (p = 0.01). The CATQUEST-9SF questionnaire showed significant differences in the variation between the preoperative condition and six-month postoperative results (p < 0.001). CONCLUSIONS: This refractive enhanced monofocal IOL can provide better intermediate vision compared to a standard monofocal IOL in patients undergoing phaco-vitrectomy due to cataracts and ERM. Further studies are necessary to confirm these results.

Full-Thickness Macular Hole: Are Supra-RPE Granular Deposits Remnants of Photoreceptors Outer Segments? Clinical Implications.

PURPOSE: To describe the presence of specific morphological characteristics of idiopathic, full-thickness macular hole (MH) potentially influencing postoperative best corrected visual acuity (BCVA) and surgical outcomes. DESIGN: Retrospective, multicenter and interventional case series. METHODS: Clinical charts and multimodal imaging pictures of 149 eyes of 143 consecutive patients diagnosed with MH, treated surgically and with a minimum follow-up of 12 months, were reviewed. RESULTS: Supra-retinal pigment epithelium (RPE) granular deposits were diagnosed in 121 of 149 eyes (81.2%). A smooth morphology was identified in 58 of 149 eyes (38.9%), whereas a bumpy border was present 91 of 149 eyes (61.1%). Photoreceptor disruption was mainly located close to the MH aperture. In 8% of the included cases, preoperative anatomical progression from smooth to bumpy morphology was noted. The presence of supra-RPE granular deposits was a significant predictor of lower postoperative BCVA only in univariate analysis (P < .001). The presence of a bumpy border was significantly correlated with lower postoperative BCVA in both univariate and multivariate analysis (P < .001). BCVA gain was significantly lower in MH with bumpy borders (P < .001). A bumpy border was also significantly associated with poor postoperative anatomical restoration (P < .001). CONCLUSIONS: Supra RPE-granular deposits and a bumpy morphology may be indicators of photoreceptor disruption in MH. A bumpy morphology may suggest deeper and potentially irreversible photoreceptor damage, and may negatively influence both functional and anatomical recovery.