ENHANCED S-CONE SYNDROME: VISUAL FUNCTION, CROSS-SECTIONAL IMAGING, AND CELLULAR STRUCTURE WITH ADAPTIVE OPTICS OPHTHALMOSCOPY.

PURPOSE: To describe in detail the phenotype of a patient with enhanced S-cone syndrome. METHODS: We describe a 13-year-old boy who presented with blurred vision, vitreous cells, cystoid macular edema refractory to steroid treatment, and a negative uveitic workup. The patient underwent a complete ophthalmic examination, full-field electroretinograms (ffERG), automatic static perimetry and multimodal imaging with spectral domain optical coherence tomography, and adaptive optics scanning laser ophthalmoscopy (AOSLO). RESULTS: Spectral domain optical coherence tomography demonstrated cystoid macular edema and a hyperthick, delaminated midperipheral retina. Fluorescein angiography did not demonstrate macular leakage. Rod-mediated ffERGs were undetectable, and there was a supernormal response to short-wavelength stimuli compared with photopically matched longer wavelengths of light consistent with enhanced S-cone syndrome. Gene screening was positive for compound heterozygous mutations NR2E3: a known (c.119-2 A>C) and a novel (c.119-1G>A) mutation. By perimetry, sensitivities were normal or above normal for short-wavelength stimuli; there was no detectable rod-mediated vision. AOSLO demonstrated higher than normal cone densities in the perifoveal retina and evidence for smaller outer segment cone diameters. CONCLUSION: Evidence for supernumerary cones (at least twice the normal complement) by AOSLO and spectral domain optical coherence tomography was associated with supernormal S-cone sensitivities and electroretinogram responses confirming previous in vivo findings in postmortem human specimens. Smaller than normal cones in enhanced S-cone syndrome may represent "hybrid" photoreceptors analogous to the rd7/rd7 murine model of the disease.

FREQUENT SUBCLINICAL MACULAR CHANGES IN COMBINED BRAF/MEK INHIBITION WITH HIGH-DOSE HYDROXYCHLOROQUINE AS TREATMENT FOR ADVANCED METASTATIC BRAF MUTANT MELANOMA: Preliminary Results From a Phase I/II Clinical Treatment Trial.

PURPOSE: To assess the potential ocular toxicity of a combined BRAF inhibition (BRAFi) + MEK inhibition (MEKi) + hydroxychloroquine (HCQ) regime used to treat metastatic BRAF mutant melanoma. METHODS: Patients with stage IV metastatic melanoma and BRAF V600E mutations (n = 11, 31-68 years of age) were included. Treatment was with oral dabrafenib, 150 mg bid, trametinib, 2 mg/day, and HCQ, 400 mg to 600 mg bid. An ophthalmic examination, spectral domain optical coherence tomography, near-infrared and short-wavelength fundus autofluorescence, and static perimetry were performed at baseline, 1 month, and q/6 months after treatment. RESULTS: There were no clinically significant ocular events; there was no ocular inflammation. The only medication-related change was a separation of the photoreceptor outer segment tip from the apical retinal pigment epithelium that could be traced from the fovea to the perifoveal retina noted in 9/11 (82%) of the patients. There were no changes in retinal pigment epithelium melanization or lipofuscin content by near-infrared fundus autofluorescence and short-wavelength fundus autofluorescence, respectively. There were no inner retinal or outer nuclear layer changes. Visual acuities and sensitivities were unchanged. CONCLUSION: BRAFi (trametinib) + MEKi (dabrafenib) + HCQ causes very frequent, subclinical separation of the photoreceptor outer segment from the apical retinal pigment epithelium without inner retinal changes or signs of inflammation. The changes suggest interference with the maintenance of the outer retinal barrier and/or phagocytic/pump functions of the retinal pigment epithelium by effective MEK inhibition.

Right Atrial Phasic Function in Heart Failure With Preserved and Reduced Ejection Fraction.

OBJECTIVES: This study researched right atrial (RA) deformation indexes and their association with all-cause mortality among subjects with or without heart failure (HF). BACKGROUND: Although left atrial dysfunction is well described in HF, patterns of RA dysfunction and their prognostic implications are unclear. Cardiac magnetic resonance (CMR) imaging can provide excellent visualization of the RA. We used CMR to characterize RA phasic function in HF and to assess its prognostic implications. METHODS: This study prospectively examined 608 adults without HF (n = 407), as well as adults with HF with a reduced ejection fraction (HFrEF) (n = 105) or with HF with a preserved ejection fraction (HFpEF) (n = 96). Phasic RA function was measured via volume measurements and feature-tracking methods to derive longitudinal strain. All-cause death was ascertained over a median follow-up of 38.9 months. Standardized hazard ratios (HRs) were computed via Cox regression. RESULTS: Measures of RA phasic function were more prominently impaired in subjects with HFrEF than those in subjects with HFpEF. In analyses that adjusted for demographic factors, HF status, left ventricular ejection fraction, right ventricular end-diastolic volume index, and right ventricular ejection fraction, RA reservoir strain (HR: 0.66; 95% confidence interval [CI]: 0.47 to 0.92; p = 0.0154), RA expansion index (HR: 0.53; 95% CI: 0.31 to 0.91; p = 0.0116), RA conduit strain (HR: 0.58; 95% CI: 0.40 to 0.84; p = 0.0039), and RA conduit strain rate (HR: 1.51; 95% CI: 1.02 to 2.220; p = 0.0373) independently predicted all-cause mortality. In contrast, RA booster pump function and RA volume index did not independently predict the risk of death. CONCLUSIONS: Phasic RA function is predictive of the risk of all-cause death in a diverse group of subjects with and without HF. RA conduit and reservoir function are independent predictors of mortality.

Left Atrial Phasic Function by Cardiac Magnetic Resonance Feature Tracking Is a Strong Predictor of Incident Cardiovascular Events.

BACKGROUND: The prognostic importance of left atrial (LA) dysfunction is increasingly recognized. Magnetic resonance imaging can provide excellent visualization of the LA wall. We aimed to study the association of LA dysfunction measured using feature-tracking magnetic resonance imaging with incident adverse cardiovascular events among subjects with or without heart failure (HF) at baseline. METHODS AND RESULTS: We prospectively studied 640 adults without HF (n=419), HF with preserved ejection fraction (n=101), or HF with reduced ejection fraction (n=120). We measured phasic LA function by volumetric and feature-tracking methods to derive longitudinal strain. The composite outcome of incident HF hospitalization or death was adjudicated during a median follow-up of 37.1 months. Measures of LA phasic function were more prominently impaired in subjects with HF with reduced ejection fraction than among subjects with HF with preserved ejection fraction. In unadjusted Cox proportional hazards models, all measures of phasic LA function and volumes (maximum, minimum, and diastatic) were associated with the composite outcome. However, in analyses that adjusted for clinical risk factors, HF status, maximum LA volume, left ventricular mass, and left ventricular ejection fraction, measures of conduit and reservoir LA function, but not booster-pump function, were associated with the composite outcome. The strongest associations were observed for conduit longitudinal strain (standardized hazard ratio, 0.66; 95% CI, 0.49-0.88; P=0.004), conduit strain rate (standardized hazard ratio, 1.59; 95% CI, 1.16-2.16; P=0.0035), and reservoir strain (standardized hazard ratio, 0.68; 95% CI, 0.52-0.89; P=0.0055). CONCLUSIONS: Phasic LA function measured using magnetic resonance imaging feature tracking is independently predictive of the risk of incident HF admission or death, even after adjusting for LA volume and left ventricular remodeling.