Leber Congenital Amaurosis Associated with Mutations in CEP290, Clinical Phenotype, and Natural History in Preparation for Trials of Novel Therapies

PURPOSE: To investigate and describe in detail the demographics, functional and anatomic characteristics, and clinical course of Leber congenital amaurosis (LCA) associated with mutations in the CEP290 gene (LCA-CEP290) in a large cohort of adults and children. DESIGN: Retrospective case series. PARTICIPANTS: Patients with mutations in CEP290 identified at a single UK referral center. METHODS: Review of case notes and results of retinal imaging (color fundus photography, fundus autofluorescence [FAF] imaging, OCT), electrophysiologic assessment, and molecular genetic testing. MAIN OUTCOME MEASURES: Molecular genetic testing, clinical findings including visual acuity and retinal imaging, and electrophysiologic assessment. RESULTS: Forty patients with LCA-CEP290 were identified. The deep intronic mutation c.2991+1655 A>G was the most common disease-causing variant (23/40 patients) identified in the compound heterozygous state in 20 patients (50%) and homozygous in 2 patients (5%). Visual acuity (VA) varied from 6/9 to no perception of light, and only 2 of 12 patients with longitudinal VA data showed deterioration in VA in their better-seeing eye over time. A normal fundus was found at diagnosis in younger patients (mean age, 1.9 years), with older patients showing white flecks (mean age, 5.9 years) or pigmentary retinopathy (mean age, 21.7 years). Eleven of 12 patients (92%) with OCT imaging had preservation of foveal architecture. Ten of 12 patients (83%) with FAF imaging had a perifoveal hyperautofluorescent ring. Having 2 nonsense CEP290 mutations was associated with worse final VA and the presence of nonocular features. CONCLUSIONS: Detailed analysis of the clinical phenotype of LCA-CEP290 in a large cohort confirms that there is a window of opportunity in childhood for therapeutic intervention based on relative structural preservation in the central cone-rich retina in a significant proportion of patients, with the majority harboring the deep intronic variant potentially tractable to several planned gene editing approaches

Lack of association of cranial lacunae with intracranial hypertension in children with Crouzon syndrome and Apert syndrome: a 3D morphometric quantitative analysis

Purpose Cranial lacunae (foci of attenuated calvarial bone) are CT equivalents ofBcopper beating seen on plain skull radio-graphs in children with craniosynostosis. The qualitative presence of copper beating has not been found to be useful for the diagnosis of intracranial hypertension (IH) in these patients. 3D morphometric analysis (3DMA) allows a more systematic and quantitative assessment of calvarial attenuation. We used 3DMA to examine the relationship between cranial lacunae and IH in children with Crouzon and Apert syndromic craniosynostosis

Visual mismatch negativity to masked stimuli presented at very brief presentation rates

Mismatch Negativity (MMN) has been characterised as a ‘pre-attentive’ component of an event-related potential (ERP) that is related to discrimination and error prediction processes. The aim of the current experiment was to establish whether visual MMN could be recorded to briefly presented, backward and forward masked visual stimuli, given both below and above levels of subjective experience. Evidence of visual MMN elicitation in the absence of the ability to consciously report stimuli would provide strong evidence for the automaticity of the visual MMN mechanism. Using an oddball paradigm, two stimuli that differed in orientation from each other, an + and an x were presented on a computer screen. Electroencephalogram (EEG) was recorded from nine participants (six females), mean age 21.4 years. Results showed that for stimuli that were effectively masked at 7ms presentation, there was little variation in the ERPs evoked to standard and deviant stimuli or in the subtraction waveform employed to delineate the visual MMN. At 14 ms stimulus presentation, when participants were able to report stimulus presence, an enhanced negativity at around 175 ms and 305 ms was observed to the deviant and was evident in the subtraction waveform. Although some of the difference observed in the ERPs can be attributed to stimulus characteristics, the use of a ‘lonely’ deviant protocol revealed attenuated visual MMN components at 14 ms stimulus presentation. Overall, results suggest that some degree of conscious attention is required before visual MMN components emerge, suggesting visual MMN is not an entirely pre-attentive process

Asymptomatic internal carotid artery stenosis and cerebrovascular risk stratification

Background The purpose of this study was to determine the cerebrovascular risk stratification potential of baseline degree of stenosis, clinical features, and ultrasonic plaque characteristics in patients with asymptomatic internal carotid artery (ICA) stenosis. Methods This was a prospective, multicenter, cohort study of patients undergoing medical intervention for vascular disease. Hazard ratios for ICA stenosis, clinical features, and plaque texture features associated with ipsilateral cerebrovascular or retinal ischemic (CORI) events were calculated using proportional hazards models. Results A total of 1121 patients with 50% to 99% asymptomatic ICA stenosis in relation to the bulb (European Carotid Surgery Trial [ECST] method) were followed-up for 6 to 96 months (mean, 48). A total of 130 ipsilateral CORI events occurred. Severity of stenosis, age, systolic blood pressure, increased serum creatinine, smoking history of more than 10 pack-years, history of contralateral transient ischemic attacks (TIAs) or stroke, low grayscale median (GSM), increased plaque area, plaque types 1, 2, and 3, and the presence of discrete white areas (DWAs) without acoustic shadowing were associated with increased risk. Receiver operating characteristic (ROC) curves were constructed for predicted risk versus observed CORI events as a measure of model validity. The areas under the ROC curves for a model of stenosis alone, a model of stenosis combined with clinical features and a model of stenosis combined with clinical, and plaque features were 0.59 (95% confidence interval [CI] 0.54-0.64), 0.66 (0.62-0.72), and 0.82 (0.78-0.86), respectively. In the last model, stenosis, history of contralateral TIAs or stroke, GSM, plaque area, and DWAs were independent predictors of ipsilateral CORI events. Combinations of these could stratify patients into different levels of risk for ipsilateral CORI and stroke, with predicted risk close to observed risk. Of the 923 patients with <70% stenosis, the predicted cumulative 5-year stroke rate was <5% in 495, 5% to 9.9% in 202, 10% to 19.9% in 142, and <20% in 84 patients. Conclusion Cerebrovascular risk stratification is possible using a combination of clinical and ultrasonic plaque features. These findings need to be validated in additional prospective studies of patients receiving optimal medical intervention alone. Copyright © 2010 by the Society for Vascular Surgery

The size of juxtaluminal hypoechoic area in ultrasound images of asymptomatic carotid plaques predicts the occurrence of stroke

Objective: To test the hypothesis that the size of a juxtaluminal black (hypoechoic) area (JBA) in ultrasound images of asymptomatic carotid artery plaques predicts future ipsilateral ischemic stroke. Methods: A JBA was defined as an area of pixels with a grayscale value &lt;25 adjacent to the lumen without a visible echogenic cap after image normalization. The size of a JBA was measured in the carotid plaque images of 1121 patients with asymptomatic carotid stenosis 50% to 99% in relation to the bulb (Asymptomatic Carotid Stenosis and Risk of Stroke study); the patients were followed for up to 8 years. Results: The JBA had a linear association with future stroke rate. The area under the receiver-operating characteristic curve was 0.816. Using Kaplan-Meier curves, the mean annual stroke rate was 0.4% in 706 patients with a JBA &lt;4 mm 2, 1.4% in 171 patients with a JBA 4 to 8 mm2, 3.2% in 46 patients with a JBA 8 to 10 mm2, and 5% in 198 patients with a JBA &gt;10 mm2 (P &lt;.001). In a Cox model with ipsilateral ischemic events (amaurosis fugax, transient ischemic attack [TIA], or stroke) as the dependent variable, the JBA (&lt;4 mm2, 4-8 mm2, &gt;8 mm2) was still significant after adjusting for other plaque features known to be associated with increased risk, including stenosis, grayscale median, presence of discrete white areas without acoustic shadowing indicating neovascularization, plaque area, and history of contralateral TIA or stroke. Plaque area and grayscale median were not significant. Using the significant variables (stenosis, discrete white areas without acoustic shadowing, JBA, and history of contralateral TIA or stroke), this model predicted the annual risk of stroke for each patient (range, 0.1%-10.0%). The average annual stroke risk was &lt;1% in 734 patients, 1% to 1.9% in 94 patients, 2% to 3.9% in 134 patients, 4% to 5.9% in 125 patients, and 6% to 10% in 34 patients. Conclusions: The size of a JBA is linearly related to the risk of stroke and can be used in risk stratification models. These findings need to be confirmed in future prospective studies or in the medical arm of randomized controlled studies in the presence of optimal medical therapy. In the meantime, the JBA may be used to select asymptomatic patients at high stroke risk for carotid endarterectomy and spare patients at low risk from an unnecessary operation

Late spontaneous recanalization of acute internal carotid artery occlusion

Spontaneous internal carotid recanalization has been infrequently observed, and when it has been reported, it has most commonly occurred early after a stroke. We report a case of a patient with late spontaneous recanalization of the internal carotid artery (ICA) that occurred within 6 months to 1 year after the initial diagnosis of occlusion during the course of a stroke. This event allowed the patient to undergo a successful surgical intervention. A suggestion is made about the mechanism of this phenomenon and an implication about changes in the follow-up strategies of these patients is presented

Recommendations for multimodal noninvasive and invasive screening for detection of extracranial venous abnormalities indicative of chronic cerebrospinal venous insufficiency: a position statement of the International Society for Neurovascular Disease

Under the auspices of the International Society for Neurovascular Disease (ISNVD), four expert panel committees were created from the ISNVD membership between 2011 and 2012 to determine and standardize noninvasive and invasive imaging protocols for detection of extracranial venous abnormalities indicative of chronic cerebrospinal venous insufficiency (CCSVI). The committees created working groups on color Doppler ultrasound (US), magnetic resonance (MR) imaging, catheter venography (CV), and intravascular US. Each group organized a workshop focused on its assigned imaging modality. Non-ISNVD members from other societies were invited to contribute to the various workshops. More than 60 neurology, radiology, vascular surgery, and interventional radiology experts participated in these workshops and contributed to the development of standardized noninvasive and invasive imaging protocols for the detection of extracranial venous abnormalities indicative of CCSVI. This ISNVD position statement presents the MR imaging and intravascular US protocols for the first time and describes refined color Doppler US and CV protocols. It also emphasizes the need for the use of for noninvasive and invasive multimodal imaging to diagnose adequately and monitor extracranial venous abnormalities indicative of CCSVI for open-label or double-blinded, randomized, controlled studies

Macrophage infiltration and smooth muscle cells content associated with haptoglobin genotype in human atherosclerotic carotid plaques

We assessed the association between the haptoglobin (Hp) genotype and 2 common indicators of atherosclerotic plaque instability: macrophage infiltration and the smooth muscle cell (SMC) content. A total of 70 consecutive patients who underwent carotid endarterectomy were included in the study. For immunohistochemical study the anti-CD68 and anti-a-actin antibodies were used on adjacent serial sections; 36 plaques from patients with the Hp 1-1 or 2-1 genotype and 34 plaques from patients with the Hp 2-2 genotype were analyzed. The macrophage content (CD68+) was significantly higher in the Hp 2-2 group compared with that in the Hp 1-1 or 2-1 group (P &lt;.001). In plaques from patients with diabetes, the SMC content was significantly lower in the Hp 2-2 group (P =.034). Carotid plaques from diabetic patients with Hp 2-2 genotype had higher macrophage infiltration and lower SMC content. Both parameters are indicators of atherosclerotic plaque instability. © 2012 SAGE Publications

Association between periodontal disease and vulnerable plaque morphology in patients undergoing carotid endarterectomy

Background: Periodontal disease (PD) is a chronic inflammatory oral condition with potentially important systemic sequelae. We sought to determine whether the presence of PD in patients with severe carotid disease was associated with morphological features consistent with carotid plaque instability. Methods: A total of 52 dentate patients hospitalized for carotid endarterectomy (CEA) had standardized assessments of their periodontal status, including measurements of probing pocket depth (PPD), clinical attachment level (CAL) and bleeding on probing (BoP). Carotid plaque morphology was assessed by ultrasound using the gray scale median (GSM) score and by immunohistochemistry using anti-CD68 and anti-alpha-actin antibodies, markers for macrophages and smooth muscle cells (SMCs) respectively. Results: In total 30/52 patients (58%) had PD. Significant associations were noted between low GSM on ultrasound and each mm in PPD (p = 0.001), each mm in CAL (p = 0.002) and with a 10% increase in BoP (p = 0.009). Using the standardized PERIO definition the association remained robust (aOR = 10.4 [95% CI:2.3–46.3], p =.002). Significant associations were also observed with high macrophage accumulation and each individual PD measure (p &lt; 0.01 for PPD, CAL and BoP) and with the PERIO definition (aOR = 15 [95% CI:1.8–127.8], p =.01). Similarly, low SMC density was also significantly associated with individual measures of PD (p &lt; 0.05 for PPD, CAL and BoP), but not with the PERIO definition (aOR 3.4 [95% CI:0.9–12.8], p =.07). Conclusions: The presence of PD was significantly associated with both ultrasound and immunohistochemistry features of carotid plaque instability in patients undergoing CEA. © 202

First in vivo application of microwave radiometry in human carotids: A new noninvasive method for detection of local inflammatory activation

Objectives: This study investigated whether temperature differences: 1) can be measured in vivo noninvasively by microwave radiometry (MR); and 2) are associated with ultrasound and histological findings. Background: Studies of human carotid artery samples showed increased heat production. MR allows in vivo noninvasive measurement of internal temperature of tissues. Methods: Thirty-four patients undergoing carotid endarterectomy underwent screening of carotid atherosclerosis by ultrasound and MR. Healthy volunteers were enrolled as a control group. During ultrasound study, plaque texture, plaque surface, and plaque echogenicity were analyzed. Temperature difference (ΔT) was assigned as maximal minus minimum temperature. Association of thermographic with ultrasound and histological findings was performed. Results: ΔT was higher in atherosclerotic carotid arteries compared with the carotid arteries of controls (p &lt; 0.01). Fatty plaques had higher ΔT compared with mixed and calcified (p &lt; 0.01) plaques. Plaques with ulcerated surface had higher ΔT compared with plaques with irregular and regular surface (p &lt; 0.01). Heterogeneous plaques had higher ΔT compared with homogenous (p &lt; 0.01). Specimens with thin fibrous cap and intense expression of CD3, CD68, and vascular endothelial growth factor (VEGF) had higher ΔT compared with specimens with thick cap and low expression of CD3, CD68, and VEGF (p &lt; 0.01). Conclusions: MR provides in vivo noninvasive temperature measurements of carotid plaques, reflecting plaque inflammatory activation. © 2012 American College of Cardiology Foundation