Dennis W. W. Shaw

Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate

We describe the development of fetal brain lesions after Zika virus (ZIKV) inoculation in a pregnant pigtail macaque. Periventricular lesions developed within 10 d and evolved asymmetrically in the occipital–parietal lobes. Fetal autopsy revealed ZIKV in the brain and significant cerebral white matter hypoplasia, periventricular white matter gliosis, and axonal and ependymal injury. Our observation of ZIKV-associated fetal brain lesions in a nonhuman primate provides a model for therapeutic evaluation.

Asymptomatic inferior vena cava abnormalities in three children withend-stage renal disease: Risk factors and screening guidelines for pretransplant diagnosis

We report two children with end‐stage renal disease (ESRD) found to have inferior vena cava (IVC) thrombosis at the time of renal transplantation. The children suffered from renal diseases that included congenital hepatic fibrosis and portal hypertension as part of their pathophysiology. Neither child had evidence of hypercoaguability or clinical symptoms of IVC thrombosis. Prior to transplantation, the renal replacement therapy consisted primarily of peritoneal dialysis. During their hospital courses, these children had central venous catheters placed for temporary hemodialysis, episodes of peritonitis and numerous abdominal surgeries. The medical literature to date has not identified a link between IVC thrombosis and portal hypertension, nor has an association between the patients’ primary renal disease and IVC thrombosis been found. We also report the finding of asymptomatic IVC narrowing in a third patient with obstructive uropathy, colonic dysmotility and numerous abdominal surgeries. IVC narrowing was diagnosed by CT scan during his pretransplant evaluation. In this paper, we consider similarities between these three patients that may have predisposed each of them to asymptomatic IVC pathology, including large‐bore central venous access as young children and/or recurrent scarring abdominal processes. A discussion regarding appropriate screening of the ‘high‐risk patient’ for IVC pathology prior to kidney transplantation and surgical options for children with this rare complication are presented.

Clinical trial preparedness in facioscapulohumeral muscular dystrophy: Clinical, tissue, and imaging outcome measures 29-30 May 2015, Rochester, New York

Clinical trial preparedness in facioscapulohumeral muscular dystrophy: Clinical, tissue, and imaging outcome measures 29–30 May 2015, Rochester, New York Rabi Tawil *, George W. Padberg , Dennis W. Shaw , Silvere M. van der Maarel , Stephen J. Tapscott , The FSHD Workshop Participants 1 a Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA b Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands c Department of Radiology, Seattle Children’s Hospital, Seattle, WA, USA d Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands e Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Skeletal Muscle Edema in Muscular Dystrophy: Clinical and Diagnostic Implications

Muscle degeneration in muscular dystrophies often includes a period of edema before fatty replacement of muscle tissue. Magnetic resonance imaging (MRI) has been used successfully to characterize muscle and fat patterns in several types of muscular dystrophies. Recent MRI techniques enable characterization of edema in tissues. This article reviews the advantages of using MRI assessment of edema and fat in muscle tissue to evaluate disease progression, and discusses inflammation and sarcolemma compromise as sources of edema in muscular dystrophy. Lastly, refining current techniques and adapting other MRI capabilities may enhance detection and assessment of edema for better evaluation of disease progression and treatment outcomes.

Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain

Zika virus (ZIKV) is a flavivirus with teratogenic effects on fetal brain, but the spectrum of ZIKV-induced brain injury is unknown, particularly when ultrasound imaging is normal. In a pregnant pigtail macaque (Macaca nemestrina) model of ZIKV infection, we demonstrate that ZIKV-induced injury to fetal brain is substantial, even in the absence of microcephaly, and may be challenging to detect in a clinical setting. A common and subtle injury pattern was identified, including (i) periventricular T2-hyperintense foci and loss of fetal noncortical brain volume, (ii) injury to the ependymal epithelium with underlying gliosis and (iii) loss of late fetal neuronal progenitor cells in the subventricular zone (temporal cortex) and subgranular zone (dentate gyrus, hippocampus) with dysmorphic granule neuron patterning. Attenuation of fetal neurogenic output demonstrates potentially considerable teratogenic effects of congenital ZIKV infection even without microcephaly. Our findings suggest that all children exposed to ZIKV in utero should receive long-term monitoring for neurocognitive deficits, regardless of head size at birth.

Clinical trial preparedness in facioscapulohumeral dystrophy: outcome measures and patient access: 8-9 April 2013, Leiden, The Netherlands.

Thirty participants from eight countries representing academic centers and advocacy groups met on 8–9 April, 2013 for a workshop on clinical trial preparedness in facioscapulohumeral muscular dystrophy (FSHD). The aims of the workshop were to discuss ways to facilitate patient access to clinical trials and to reach consensus on the development of the most appropriate clinical and surrogate outcome measures for future clinical trials. FSHD is one of the most common forms of muscular dystrophy with a prevalence of 1:15,000–1:20,000 [1,2]. A dominantly inherited disease, in its most common form, FSHD is slowly progressive and causes significant lifetime morbidity, with up to 20% above age 50 requiring full time wheelchair use. The clinical spectrum of disease severity is wide and the regional distribution of muscle weakness and the pattern of progression are unique. Muscle weakness typically starts in the face and shoulders, often with striking side-to-side asymmetry, with a descending progression to involve first the distal lower extremity muscle before affecting the hip girdle muscles. Non muscular involvement in FSHD includes hearing loss and retinal vascular disease, which are typically symptomatic only in patients with the largest deletions.

Patch-based augmentation of Expectation-Maximization for brain MRI tissue segmentation at arbitrary age after premature birth.

Accurate automated tissue segmentation of premature neonatal magnetic resonance images is a crucial task for quantification of brain injury and its impact on early postnatal growth and later cognitive development. In such studies it is common for scans to be acquired shortly after birth or later during the hospital stay and therefore occur at arbitrary gestational ages during a period of rapid developmental change. It is important to be able to segment any of these scans with comparable accuracy. Previous work on brain tissue segmentation in premature neonates has focused on segmentation at specific ages. Here we look at solving the more general problem using adaptations of age specific atlas based methods and evaluate this using a unique manually traced database of high resolution images spanning 20 gestational weeks of development. We examine the complimentary strengths of age specific atlas-based Expectation-Maximization approaches and patch-based methods for this problem and explore the development of two new hybrid techniques, patch-based augmentation of Expectation-Maximization with weighted fusion and a spatial variability constrained patch search. The former approach seeks to combine the advantages of both atlas- and patch-based methods by learning from the performance of the two techniques across the brain anatomy at different developmental ages, while the latter technique aims to use anatomical variability maps learnt from atlas training data to locally constrain the patch-based search range. The proposed approaches were evaluated using leave-one-out cross-validation. Compared with the conventional age specific atlas-based segmentation and direct patch based segmentation, both new approaches demonstrate improved accuracy in the automated labeling of cortical gray matter, white matter, ventricles and sulcal cortical-spinal fluid regions, while maintaining comparable results in deep gray matter.

Callosal alterations in pyridoxine-dependent epilepsy

While there have been isolated reports of callosal morphology differences in pyridoxine‐dependent epilepsy (PDE), a rare autosomal disorder caused by ALDH7A1 gene mutations, no study has systematically evaluated callosal features in a large sample of patients. This study sought to overcome this knowledge gap.

Imaging Evidence for Pathological Brain Development in Autism Spectrum Disorders

Though much has been learned about autism spectrum disorders (ASD) during the past decade, the mechanisms underlying ASD remain an enigma. One of the more consistent brain anatomical findings associated with ASD has been larger brains, on average 10–15% enlargement by magnetic resonance imaging (MRI), in preschool-aged children evaluated soon after clinical diagnosis. It is the premise of this chapter that research investigating cellular composition in ASD in vivo can elucidate aspects of the underlying pathophysiology, such as the phenomenon of early brain enlargement in ASD, and help guide ongoing theoretical model development. This chapter will review applications of magnetic resonance spectroscopy (MRS) and magnetic resonance transverse relaxation techniques (T2r) used in an attempt to elucidate developmental mechanisms underlying brain structural alterations in ASD. For example, one hypothesis put forth to explain findings of brain enlargement in ASD has implicated alterations in the complicated biochemistry governing apoptosis and/or synaptic pruning, with resultant neuronal “overgrowth.” However, studies from our laboratory of brain chemical alterations in preschool-aged ASD children instead have found evidence for decreased neuronal compactness or density, contradictory to such theories. Another theory to explain observations of early but not later brain enlargement in ASD suggests accelerated “normal” brain growth, which then decelerates or plateaus before the time course of brain growth for typically developing children. Contrary to this theory, our recent quantitative T2r study, designed to characterize the temporal progression of brain maturation, implicates mechanism(s) other than more rapid growth to account for larger brains in ASD. Although these research findings cannot be considered diagnostic, they do provide new insights for pursuing mechanisms underlying ASD.

Preserved interhemispheric functional connectivity in a case of corpus callosum agenesis

Dear Sir, Functional connectivity MRI (fcMRI) evaluates patterns of spontaneous modulations in blood oxygen leveldependent (BOLD) signal during rest. In contrast, the task-related functional MRI (fMRI) approach measures BOLD changes that occur in response to a task [1]. The study of functional connectivity arose from the observation that spontaneous fluctuations measured in the left somatomotor cortex are correlated with spontaneous fluctuations in the right somatomotor cortex and within medial motor areas in the absence of overt motor behavior [2]. Similar results have been found in multiple other networks [3–7], including visual, auditory, language, dorsal and ventral attention systems, and corticothalamic circuits. Studies of fcMRI have provided insight into the functional organization of the brain and have been used to probe the role of the corpus callosum in mediating restingstate activity [8–10]. A study [8] of three adult subjects with agenesis of the corpus callosum (ACC) found that bilateral connectivity in the motor and auditory cortices was absent or greatly diminished compared to that of normal controls. Another study [9] reported that dorsal attention, default, and primary visual neural systems demonstrated a near-complete loss in bilateral functional connectivity after callosotomy. On the other hand, 45 years after complete commissurotomy, bilateral connectivity was observed in a single patient, suggesting that connectivity deficits may resolve over time [10]. We explored functional connectivity in a patient with near-complete ACC. Our patient, a 6-year-old male, was imaged under propofol anesthesia on a 3 T (Siemens MAGNETOM Trio) system using a 32-channel head coil (Fig. 1). Diffusion tensor imaging (DTI) and restingstate fMRI data were acquired. Postprocessing of fcMRI