Mechanistically distinct mouse models for CRX-associated retinopathy.

Cone-rod homeobox (CRX) protein is a "paired-like" homeodomain transcription factor that is essential for regulating rod and cone photoreceptor transcription. Mutations in human CRX are associated with the dominant retinopathies Retinitis Pigmentosa (RP), Cone-Rod Dystrophy (CoRD) and Leber Congenital Amaurosis (LCA), with variable severity. Heterozygous Crx Knock-Out (KO) mice ("+/-") have normal vision as adults and fail to model the dominant human disease. To investigate how different mutant CRX proteins produce distinct disease pathologies, we generated two Crx Knock-IN (K-IN) mouse models: Crx(E168d2) ("E168d2") and Crx(R90W) ("R90W"). E168d2 mice carry a frameshift mutation in the CRX activation domain, Glu168del2, which is associated with severe dominant CoRD or LCA in humans. R90W mice carry a substitution mutation in the CRX homeodomain, Arg90Trp, which is associated with dominant mild late-onset CoRD and recessive LCA. As seen in human patients, heterozygous E168d2 ("E168d2/+") but not R90W ("R90W/+") mice show severely impaired retinal function, while mice homozygous for either mutation are blind and undergo rapid photoreceptor degeneration. E168d2/+ mice also display abnormal rod/cone morphology, greater impairment of CRX target gene expression than R90W/+ or +/- mice, and undergo progressive photoreceptor degeneration. Surprisingly, E168d2/+ mice express more mutant CRX protein than wild-type CRX. E168d2neo/+, a subline of E168d2 with reduced mutant allele expression, displays a much milder retinal phenotype, demonstrating the impact of Crx expression level on disease severity. Both CRX([E168d2]) and CRX([R90W]) proteins fail to activate transcription in vitro, but CRX([E168d2]) interferes more strongly with the function of wild type (WT) CRX, supporting an antimorphic mechanism. E168d2 and R90W are mechanistically distinct mouse models for CRX-associated disease that will allow the elucidation of molecular mechanisms and testing of novel therapeutic approaches for different forms of CRX-associated disease.

Correlation between papilledema grade and diffusion-weighted magnetic resonance imaging in idiopathic intracranial hypertension.

BACKGROUND: To explore the relationship between diffusion-weighted magnetic resonance imaging (DWI) hyperintensity of the optic nerve head (ONH) and papilledema grade in patients with idiopathic intracranial hypertension (IIH). METHODS: A retrospective chart review was conducted of patients with definitively diagnosed IIH by clinical examination and visual field (VF) analysis who underwent orbital magnetic resonance imaging (MRI) within 4 weeks of diagnosis. A neuroradiologist masked to the diagnosis assessed the results of DWI for each eye independently and graded the signal intensity of the ONH into none, mild, and prominent categories. DWI grading was compared with papilledema grade and visual field mean deviation (VFMD) by Spearman rank correlation analysis and t-tests. RESULTS: Forty-two patients were included in the study. A statistically significant difference (P = 0.0195) was found between papilledema grade and patients with prominent DWI findings (n = 16; mean papilledema grade 3.75 ± 1.25) vs mild or no ONH hyperintensity (n = 26; mean papilledema grade 2.79 ± 1.24) at the time of initial diagnosis. DWI hyperintensity of the ONH at diagnosis was also found to be significantly correlated with the degree of papilledema at follow-up (ρ = 0.39, P = 0.0183) but not with VFMD. CONCLUSIONS: We found a significant correlation between the severity of papilledema and ONH hyperintensity on DWI in patients with IIH but not with VF loss or other visual parameters. These findings may offer insight into the pathophysiology of papilledema in IIH and provide a surrogate marker for the presence and severity of papilledema.

Association between visual parameters and neuroimaging features of idiopathic intracranial hypertension.

BACKGROUND/AIMS: Papilledema refers to optic disc swelling resulting from high intracranial pressure (ICP). The precise mechanism by which papilledema occurs remains uncertain. Although orbital neuroimaging features associated with papilledema are well-described, it is unclear whether these findings correlate with visual function. Idiopathic Intracranial Hypertension (IIH) is a condition in which the intracranial pressure is elevated with no obvious cause, causing papilledema and visual loss. The utility of papilledema and IIH neuroimaging findings as a surrogate marker for visual loss, or a predictor of visual loss, is understudied. This retrospective cross-sectional review aims to correlate parameters of visual function with orbital magnetic resonance imaging (MRI) findings. METHODS: Patients meeting criteria for IIH who had received orbital imaging within 4 weeks of examination were included. Visual parameters of papilledema grade, visual field mean deviation, and visual acuity were correlated with neuroimaging features, including optic nerve thickness, and optic nerve sheath thickness, among others. All MRI scans were reviewed by a neuroradiologist blinded to clinical status. Spearman rank correlations and t-tests were generated with SAS (v9.2). RESULTS: Thirty five patients were included. No significant relationships were found between the main visual parameters of papilledema grade and visual field mean deviation, and MRI findings. CONCLUSIONS: We found no significant correlation between visual parameters and imaging features of papilledema. This might indicate that MRI features may provide insight into the structural changes that occur in papilledema, but may not be helpful when making clinical management decisions for patients with IIH in particular, and papilledema in general.