Brachial Plexus Nerve Block with CT Guidance for Regional Pain Management: Initial Results

Brachial plexus nerve blocks are performed to treat patients with chronic pain referable to the brachial plexus. The needle insertion and trajectory are based on palpation of surface landmarks. Occasionally, the surface landmarks are difficult to identify owing to body habitus or anatomic alterations secondary to surgery or radiation therapy. The intent of this manuscript is to describe a technique for brachial plexus block guided with computed tomography and to report our initial results for regional pain management

Autonomic nervous system involvement in the giant axonal neuropathy (GAN) KO mouse: implications for human disease

Giant axonal neuropathy (GAN) is an inherited severe sensorimotor neuropathy. The aim of this research was to investigate the neuropathologic features and clinical autonomic nervous system (ANS) phenotype in two GAN knockout (KO) mouse models. Little is known about ANS involvement in GAN in humans, but autonomic signs and symptoms are commonly reported in early childhood

A Toolkit for Pediatric CT Dose Reduction in Community Hospitals

"Eighty percent of success is just showing up."—Woody Allen Pediatric CT radiation dose optimization is a challenging process for pediatric-focused facilities and community hospitals alike. Ongoing experience and trial-and-error approaches to dose reduction in the large academic hospital setting may position these centers to help community hospitals that strive for CT quality improvement. We describe our hands-on approach in a pilot project to create a partnership between an academic medical center and a community hospital to develop a toolkit for implementing CT dose reduction. Our aims were to (1) assess the acceptability of an interactive educational program and electronic toolkit booklet, (2) conduct a limited test of the efficacy of the toolkit in promoting knowledge and readiness to change, and (3) assess the acceptability and practicality of a collaborative approach to implementing dose reduction protocols in community hospitals. In partnering with the community hospital, we found that they had size-specific radiation doses two to three times higher than those at our center. Survey results after a site visit with interactive educational presentations revealed an increase in knowledge, stronger opinions about the health risks of radiation from CT scans, and willingness and perceived ability to reduce pediatric CT doses

More insights into early brain development through statistical analyses of eigen-structural elements of diffusion tensor imaging using multivariate adaptive regression splines

The aim of this study was to characterize the maturational changes of the three eigenvalues (λ1 ≥ λ2 ≥ λ3) of diffusion tensor imaging (DTI) during early postnatal life for more insights into early brain development. In order to overcome the limitations of using presumed growth trajectories for regression analysis, we employed Multivariate Adaptive Regression Splines (MARS) to derive data-driven growth trajectories for the three eigenvalues. We further employed Generalized Estimating Equations (GEE) to carry out statistical inferences on the growth trajectories obtained with MARS. With a total of 71 longitudinal datasets acquired from 29 healthy, full-term pediatric subjects, we found that the growth velocities of the three eigenvalues were highly correlated, but significantly different from each other. This paradox suggested the existence of mechanisms coordinating the maturations of the three eigenvalues even though different physiological origins may be responsible for their temporal evolutions. Furthermore, our results revealed the limitations of using the average of λ2 and λ3 as the radial diffusivity in interpreting DTI findings during early brain development because these two eigenvalues had significantly different growth velocities even in central white matter. In addition, based upon the three eigenvalues, we have documented the growth trajectory differences between central and peripheral white matter, between anterior and posterior limbs of internal capsule, and between inferior and superior longitudinal fasciculus. Taken together, we have demonstrated that more insights into early brain maturation can be gained through analyzing eigen-structural elements of DTI

Longitudinal regression analysis of spatial–temporal growth patterns of geometrical diffusion measures in early postnatal brain development with diffusion tensor imaging

Although diffusion tensor imaging (DTI) has provided substantial insights into early brain development, most DTI studies based on fractional anisotropy (FA) and mean diffusivity (MD) may not capitalize on the information derived from the three principal diffusivities (e.g. eigenvalues). In this study, we explored the spatial and temporal evolution of white matter structures during early brain development using two geometrical diffusion measures, namely, linear (Cl) and planar (Cp) diffusion anisotropies, from 71 longitudinal datasets acquired from 29 healthy, full-term pediatric subjects. The growth trajectories were estimated with generalized estimating equations (GEE) using linear fitting with logarithm of age (days). The presence of the white matter structures in Cl and Cp was observed in neonates, suggesting that both the cylindrical and fanning or crossing structures in various white matter regions may already have been formed at birth. Moreover, we found that both Cl and Cp evolved in a temporally nonlinear and spatially inhomogeneous manner. The growth velocities of Cl in central white matter were significantly higher when compared to peripheral, or more laterally located, white matter: central growth velocity Cl = 0.0465±0.0273/log(days), versus peripheral growth velocity Cl=0.0198±0.0127/log(days), p−6. In contrast, the growth velocities of Cp in central white matter were significantly lower than that in peripheral white matter: central growth velocity Cp= 0.0014±0.0058/log(days), versus peripheral growth velocity Cp = 0.0289±0.0101/log(days), p−6. Depending on the underlying white matter site which is analyzed, our findings suggest that ongoing physiologic and microstructural changes in the developing brain may exert different effects on the temporal evolution of these two geometrical diffusion measures. Thus, future studies utilizing DTI with correlative histological analysis in the study of early brain development are warranted

Advancing the pathologic phenotype of giant axonal neuropathy: early involvement of the ocular lens

Abstract Giant axonal neuropathy (GAN; ORPHA: 643; OMIM# 256850) is a rare, hereditary, pediatric neurodegenerative disorder associated with intracellular accumulations of intermediate filaments (IFs). GAN knockout (KO) mouse models mirror the IF dysregulation and widespread nervous system pathology seen in human GAN. Validation of therapeutic efficacy and viral vector delivery systems with these GAN KO models has provided the springboard for the development of a viral vector being delivered intrathecally in an ongoing Phase I gene therapy clinical trial for the treatment of children with GAN ( https://clinicaltrials.gov/ct2/show/NCT02362438 ). During the course of a comprehensive pathologic characterization of the GAN KO mouse, we discovered the very early and unexpected involvement of the ocular lens. Light microscopy revealed the presence of intracytoplasmic inclusion bodies within lens epithelial cells. The inclusion bodies showed strong immunohistochemical positivity for glial fibrillary acidic protein (GFAP). We confirmed that intracytoplasmic inclusion bodies are also present within lens epithelial cells in human GAN. These IF inclusion bodies in lens epithelial cells are unique to GAN. Similar IF inclusion bodies in lens epithelial cells have not been reported previously in experimental animal models or human diseases. Since current paradigms in drug discovery and drug repurposing for IF-associated disorders are often hindered by lack of validated targets, our findings suggest that lens epithelial cells in the GAN KO mouse may provide a potential target, in vivo and in vitro, for evaluating drug efficacy and alternative therapeutic approaches in promoting the clearance of IF inclusions in GAN and other diseases characterized by intracellular IF accumulations

Diffusion tensor imaging based network analysis detects alterations of neuroconnectivity in patients with clinically early relapsing-remitting multiple sclerosis: Network Analysis Detects Neuroconnectivity Alterations in Early Relapsing Remitting MS

Although it is inarguable that conventional MRI (cMRI) has greatly contributed to the diagnosis and assessment of Multiple Sclerosis (MS), cMRI does not show close correlation with clinical findings or pathologic features, and is unable to predict prognosis or stratify disease severity. To this end, diffusion tensor imaging (DTI) with tractography and neuroconnectivity analysis may assist disease assessment in MS. We therefore attempted this pilot study for initial assessment of early relapsing remitting (RR) MS. Neuroconnectivity analysis was employed for evaluation of 24 early RRMS patients within two years of presentation, and compared to the network measures of a group of 30 age-and-gender-matched normal control subjects. To account for the situation that the connections between two adjacent regions may be disrupted by an MS lesion, a new metric, network communicability, was adopted to measure both direct and indirect connections. For each anatomical area, the brain network communicability and average path length (APL) were computed and compared to characterize the network changes in efficiencies. Statistically significant (p < 0.05) loss of communicability was revealed in our RRMS cohort, particularly in the frontal and hippocampal/parahippocampal regions as well as the motor strip and occipital lobes. Correlation with the 25 foot walk test with communicability measures in the left superior frontal (r = -0.71) as well as the left superior temporal gyrus (r = -0.43) and left postcentral gyrus (r = -0.41) were identified. Additionally identified were increased communicability between the deep gray matter (GM) structures (left thalamus and putamen) with the major inter-hemispheric and intra-hemispheric white matter tracts, the corpus callosum and cingulum respectively. These foci of increased communicability are thought to represent compensatory changes. The proposed DTI based neuroconnectivity analysis demonstrated quantifiable, structurally relevant alterations of fiber tract connections in early relapsing remitting MS and paves the way for longitudinal studies in larger patient groups

Development of Intrathecal AAV9 Gene Therapy for Giant Axonal Neuropathy

An NIH-sponsored phase I clinical trial is underway to test a potential treatment for giant axonal neuropathy (GAN) using viral-mediated GAN gene replacement (https://clinicaltrials.gov/ct2/show/NCT02362438). This trial marks the first instance of intrathecal (IT) adeno-associated viral (AAV) gene transfer in humans. GAN is a rare pediatric neurodegenerative disorder caused by autosomal recessive loss-of-function mutations in the GAN gene, which encodes the gigaxonin protein. Gigaxonin is involved in the regulation, turnover, and degradation of intermediate filaments (IFs). The pathologic signature of GAN is giant axonal swellings filled with disorganized accumulations of IFs. Herein, we describe the development and characterization of the AAV vector carrying a normal copy of the human GAN transgene (AAV9/JeT-GAN) currently employed in the clinical trial. Treatment with AAV/JeT-GAN restored the normal configuration of IFs in patient fibroblasts within days in cell culture and by 4 weeks in GAN KO mice. IT delivery of AAV9/JeT-GAN in aged GAN KO mice preserved sciatic nerve ultrastructure, reduced neuronal IF accumulations and attenuated rotarod dysfunction. This strategy conferred sustained wild-type gigaxonin expression across the PNS and CNS for at least 1 year in mice. These results support the clinical evaluation of AAV9/JeT-GAN for potential therapeutic outcomes and treatment for GAN patients. Keywords: gene therapy, adeno-associated virus, giant axonal neuropathy, AAV9, intrathecal, fibroblast, dorsal root ganglia, sciatic nerve, gigaxonin, biodistributio

Autosomal dominant polycystic kidney disease: MR imaging evaluation using current techniques

To determine the MR imaging findings of autosomal dominant polycystic kidney disease using current imaging techniques. We reviewed our five-year experience with MR imaging of autosomal dominant polycystic kidney disease (ADPKD) to determine the spectrum of appearance of kidney disease, the occurrence of cysts in other abdominal organs, the size and number of cysts in the kidneys and other organs, and the association with other benign or malignant disease. Thirty patients (17 men and 13 women, age range 30 to 88 years old) with ADPKD were included in this study. All patients were examined by MR imaging including T2-weighted single-shot echo-train spin-echo and pre- and post-gadolinium chelate spoiled gradient-echo imaging. All kidneys were involved with multiple, varying sized cysts scattered throughout the parenchyma. Giant renal cysts (>8 cm) were associated with pain in the only two patients who possessed them. Hemorrhage in renal cysts was observed in all kidneys with a heterogeneous pattern of involvement on non-contrast T1- and T2-weighted images, reflecting hemorrhage of varying age. The mean kidney size for the right kidney was 17.4 cm in length, 10.3 cm in transverse, and 9.4 cm in antero-posterior diameter (AP); and for the left kidney, 15.9 cm in the length, 9.3 cm in the transverse, and 9.3 cm in AP diameter. Other organs involved included the liver (22 patients), the pancreas (three patients), with two of the above-mentioned patients having both liver and pancreas cysts, and the spleen (one patient) who had both liver and splenic cysts. Massive liver involvement with large cysts was associated with abdominal pain. Malignant disease was present in five patients, including two patients with renal cell carcinoma, one with bladder cancer, one with lung cancer, and one patient with anal adenocarcinoma. Comparison of pre- and post-contrast T1-weighted images was essential to detect renal cancer. All kidneys in patients with ADPKD had extensive, varying-sized cysts and in all cases some cysts showed evidence of hemorrhage. The liver was the second most common organ to be involved with cystic disease, in 73% of patients. Large cysts in the kidneys and liver were associated with abdominal pain