A. J. Barkovich

Neural Stem Cell Engraftment and Myelination in the Human Brain

Neural stem cell transplantation study suggests myelin formation in children with a severe hypomyelination disorder. Bringing Insulation Up to Code Faulty insulation around household wiring is an electric shock and fire hazard; likewise, defects in the insulation around nerve fibers—the myelin sheath—can have destructive effects. Because of myelin’s crucial roles in promoting the rapid transmission of nerve impulses and in axon integrity, mutations that affect myelin formation in the central nervous system cause severe neurological decline. Uchida et al. and Gupta et al. now investigate the use of neural stem cells—which can differentiate into myelin-producing oligodendrocytes—as a potential treatment for such disorders. Previous work showed that transplantation of human oligodendrocyte progenitors into newborn shiverer (Shi) mice, a hypomyelination model, could prolong survival. In the new work, Uchida et al. transplanted human neural stem cells, which had been expanded and banked, into the brains of newborn and juvenile Shi mice. Whereas the newborn mice were asymptomatic, the juvenile mice were already symptomatic and displayed advanced dysmyelination. These transplanted cells preferentially differentiated into oligodendrocytes that generated myelin, which ensheathed axons and improved nerve conduction in both categories of mice. In an open-label phase 1 study, Gupta et al. then tested the safety and efficacy of such cells in four young boys with a severe, fatal form of Pelizaeus-Merzbacher disease (PMD), a rare X-linked condition in which oligodendrocytes cannot myelinate axons. Human neural stem cells were transplanted directly into the brain; the procedure and transplantation were well tolerated. Magnetic resonance imaging techniques, performed before transplant and five times in the following year, were used to assess myelination. The imaging results were consistent with donor cell–derived myelination in the transplantation region in three of the four patients. These results support further study of potential clinical benefits of neural stem cell transplantation in PMD and other dysmyelination disorders. Pelizaeus-Merzbacher disease (PMD) is a rare leukodystrophy caused by mutation of the proteolipid protein 1 gene. Defective oligodendrocytes in PMD fail to myelinate axons, causing global neurological dysfunction. Human central nervous system stem cells (HuCNS-SCs) can develop into oligodendrocytes and confer structurally normal myelin when transplanted into a hypomyelinating mouse model. A 1-year, open-label phase-1 study was undertaken to evaluate safety and to detect evidence of myelin formation after HuCNS-SC transplantation. Allogeneic HuCNS-SCs were surgically implanted into the frontal lobe white matter in four male subjects with an early-onset severe form of PMD. Immunosuppression was administered for 9 months. Serial neurological evaluations, developmental assessments, and cranial magnetic resonance imaging (MRI) and MR spectroscopy, including high-angular resolution diffusion tensor imaging (DTI), were performed at baseline and after transplantation. The neurosurgical procedure, immunosuppression regimen, and HuCNS-SC transplantation were well tolerated. Modest gains in neurological function were observed in three of the four subjects. No clinical or radiological adverse effects were directly attributed to the donor cells. Reduced T1 and T2 relaxation times were observed in the regions of transplantation 9 months after the procedure in the three subjects. Normalized DTI showed increasing fractional anisotropy and reduced radial diffusivity, consistent with myelination, in the region of transplantation compared to control white matter regions remote to the transplant sites. These phase 1 findings indicate a favorable safety profile for HuCNS-SCs in subjects with PMD. The MRI results suggest durable cell engraftment and donor-derived myelin in the transplanted host white matter.

Predictors of outcome in perinatal arterial stroke: A population-based study

Some infants with perinatal arterial ischemic stroke (PAS) experience development of cerebral palsy (CP), epilepsy, and cognitive impairment, whereas others have a normal outcome. Previous prognostic studies rarely have included all diagnosed cases of PAS within a population. Among 199,176 infants born within Kaiser Permanente from 1997 to 2002, we electronically identified head imaging reports and physician diagnoses suggesting stroke. The diagnosis of PAS was confirmed by review of brain imaging and medical records. Presentation of PAS was considered delayed if symptoms were only noted after 28 days. Outcomes were determined by chart review. Of 40 infants with PAS, 36 were observed over 12 months. Abnormal outcomes included CP (58%), epilepsy (39%), language delay (25%), and behavioral abnormalities (22%). A delayed presentation was associated with increased risk for CP (relative risk [RR], 2.2; 95% confidence interval [CI], 1.2–4.2). Radiological predictors of CP included large stroke size (RR, 2.0; 95% CI, 1.2–3.2) and injury to Brocas area (RR, 2.5; 95% CI, 1.3–5.0), internal capsule (RR, 2.2; 95% CI, 1.1–4.4), Wernickes area (RR, 2.0; 95% CI, 1.1–3.8), or basal ganglia (RR, 1.9; 95% CI, 1.1–3.3). Among infants with PAS, specific radiological findings and a lack of symptoms in the newborn period are associated with increased risk for CP. Ann Neurol 2005

Giant congenital melanocytic nevi: the significance of neurocutaneous melanosis in neurologically asymptomatic children.

Patients with a giant congenital melanocytic nevus can develop melanotic tumors characterized by central nervous system involvement, termed leptomeningeal melanocytosis or neurocutaneous melanosis. Although symptomatic neurocutaneous melanosis is rare, we previously reported distinct magnetic resonance (MR) findings of T1 shortening, strongly suggestive of neurocutaneous melanosis, in 30 percent (6 of 20) of children with giant congenital melanocytic nevi who presented initially without neurological symptoms. The purpose of this study was to determine the incidence of neurocutaneous melanosis in high‐risk patients and its long‐term clinical significance. Magnetic resonance imaging was recommended for all 46 patients with “at‐risk” giant congenital melanocytic nevi involving the skin overlying the dorsal spine or scalp. The clinical histories and follow‐up of these patients were evaluated by retrospective chart review. Forty‐two underwent MR imaging of the brain and 11 underwent additional MR scanning of the spinal cord. Abnormalities were identified in 14 of 43 MR studies, and 23 percent (n = 10) had T1 shortening indicative of melanotic rests within the brain or meninges. None had associated masses or leptomeningeal thickening. The most common areas of involvement in these 10 included the amygdala (n = 8), cerebellum (n = 5), and pons (n = 3). In the group of 11 patients with spinal MR scans, a tethered spinal cord was demonstrated in one. Additional abnormalities were detected by MR scanning, including a middle cranial fossa arachnoid cyst, a Chiari type I malformation, and a crescentic enhancement that subsequently resolved. Clinical follow‐up averaging 5 years (range, 2 to 8 years) revealed that only one of the 46 patients evaluated developed neurological symptoms, manifested as developmental delay, hypotonia, and questionable seizures but no other signs of neurocutaneous melanosis. No patient has developed a cutaneous or central nervous system melanoma. Magnetic resonance findings of neurocutaneous melanosis are relatively common, even in asymptomatic children with giant congenital melanocytic nevi. Although these findings suggest an increased lifetime risk of central nervous system melanoma, they do not signify the eventual development of symptomatic neurocutaneous melanosis during childhood. (Plast. Reconstr. Surg. 107: 933, 2001.)

Giant congenital melanocyte nevi: Brain magnetic resonance findings in neurologically asymptomatic children

BACKGROUNDnPatients with giant or multiple congenital melanocytic nevi occasionally have leptomeningeal melanocytosis, also called neurocutaneous melanosis (NCM). Patients with symptomatic NCM usually have signs or symptoms of increased intracranial pressure and have a poor prognosis. Magnetic resonance (MR) imaging is sensitive in detecting melanin; several recent reports have described the MR findings in neurocutaneous melanosis.nnnOBJECTIVEnThe aim of this study is to review the brain MR findings and their potential significance in a group of neurologically asymptomatic children with giant congenital melanocytic nevi at risk for the development of NCM.nnnMETHODSnRetrospective review of patient charts and MR studies was performed.nnnRESULTSnNine of the 20 patients evaluated had MR abnormalities: six had focal areas of high signal on T1-weighted images, strongly suggestive of melanosis, in one or multiple areas of the brain including the temporal lobes, cerebellum, pons, and medulla. One had a middle cranial fossa arachnoid cyst; another had a Chiari type I malformation of the brain. In one patient a crescentic enhancement over the right parietal region, probably from perinatal trauma, was absent on repeat MR 6 months later. In no case was thickening of the leptomeninges or spinal abnormalities noted.nnnCONCLUSIONSnNCM may be much more common than previously suspected in patients with giant congenital melanocytic nevi. The most common finding on MR appears to be T1 shortening in the cerebellum, temporal lobes, pons, and medulla, rather than evidence of leptomeningeal thickening. These findings may have implications for management of patients with giant CMN.

Intersection Based Motion Correction of Multislice MRI for 3-D in Utero Fetal Brain Image Formation

In recent years, postprocessing of fast multislice magnetic resonance imaging (MRI) to correct fetal motion has provided the first true 3-D MR images of the developing human brain in utero. Early approaches have used reconstruction based algorithms, employing a two-step iterative process, where slices from the acquired data are realigned to an approximate 3-D reconstruction of the fetal brain, which is then refined further using the improved slice alignment. This two step slice-to-volume process, although powerful, is computationally expensive in needing a 3-D reconstruction, and is limited in its ability to recover subvoxel alignment. Here, we describe an alternative approach which we term slice intersection motion correction (SIMC), that seeks to directly co-align multiple slice stacks by considering the matching structure along all intersecting slice pairs in all orthogonally planned slices that are acquired in clinical imaging studies. A collective update scheme for all slices is then derived, to simultaneously drive slices into a consistent match along their lines of intersection. We then describe a 3-D reconstruction algorithm that, using the final motion corrected slice locations, suppresses through-plane partial volume effects to provide a single high isotropic resolution 3-D image. The method is tested on simulated data with known motions and is applied to retrospectively reconstruct 3-D images from a range of clinically acquired imaging studies. The quantitative evaluation of the registration accuracy for the simulated data sets demonstrated a significant improvement over previous approaches. An initial application of the technique to studying clinical pathology is included, where the proposed method recovered up to 15 mm of translation and 30? of rotation for individual slices, and produced full 3-D reconstructions containing clinically useful additional information not visible in the original 2-D slices.

Magnetic resonance techniques in the assessment of myelin and myelination.

SummaryLeukodystrophy is a common central nervous system manifestation of inborn errors of metabolism. Until magnetic resonance imaging (MRI) emerged as a clinical tool, the diagnosis of leukodystrophy was difficult and imprecise; MRI has allowed new understandings and classifications of leukodystrophies that have greatly enhanced both our diagnostic ability and our understanding of these complex disorders. However, optimal use of MRI in this setting requires a fundamental understanding of myelin structure, myelin development, and the changes seen on MRI with myelination and demyelination. The purpose of this review is to provide the reader with the necessary tools for the use of MRI to diagnose and follow patients with leukodystrophies.

Multiple risk factors in neonatal sinovenous thrombosis

Abstract—The etiology of neonatal sinovenous thrombosis is poorly understood. The authors report the risk factors and radiologic features of neonatal sinovenous thrombosis seen over an 11-year period. Of 30 patients, 29% received extracorporeal membrane oxygenation treatment, and 23% had congenital heart disease. Genetic thrombophilias were present in four of the seven infants tested. Eighteen neonates had multiple maternal, neonatal, perinatal, or prothrombotic complications. Sinovenous thrombosis was often accompanied by infarction (50%) or intraventricular hemorrhage (33%).

Clinically silent preoperative brain injuries do not worsen with surgery in neonates with congenital heart disease.

OBJECTIVEnPreoperative brain injury, particularly stroke and white matter injury, is common in neonates with congenital heart disease. The objective of this study was to determine the risk of hemorrhage or extension of preoperative brain injury with cardiac surgery.nnnMETHODSnThis dual-center prospective cohort study recruited 92 term neonates, 62 with transposition of the great arteries and 30 with single ventricle physiology, from 2 tertiary referral centers. Neonates underwent brain magnetic resonance imaging scans before and after cardiac surgery.nnnRESULTSnBrain injury was identified in 40 (43%) neonates on the preoperative magnetic resonance imaging scan (median 5 days after birth): stroke in 23, white matter injury in 21, and intraventricular hemorrhage in 7. None of the brain lesions presented clinically with overt signs or seizures. Preoperative brain injury was associated with balloon atrial septostomy (P = .003) and lowest arterial oxygen saturation (P = .007); in a multivariable model, only the effect of balloon atrial septostomy remained significant when adjusting for lowest arterial oxygen saturation. On postoperative magnetic resonance imaging in 78 neonates (median 21 days after birth), none of the preoperative lesions showed evidence of extension or hemorrhagic transformation (0/40 [95% confidence interval: 0%-7%]). The presence of preoperative brain injury was not a significant risk factor for acquiring new injury on postoperative magnetic resonance imaging (P = .8).nnnCONCLUSIONSnClinically silent brain injuries identified preoperatively in neonates with congenital heart disease, including stroke, have a low risk of progression with surgery and cardiopulmonary bypass and should therefore not delay clinically indicated cardiac surgery. In this multicenter cohort, balloon atrial septostomy remains an important risk factor for preoperative brain injury, particularly stroke.

l-2-Hydroxyglutaric aciduria: Neuropathological correlations and first report of severe neurodegenerative disease and neonatal death

Summaryl-2-Hydroxyglutaric aciduria is a rare organic aciduria associated with neurological and particularly cerebellar abnormalities. These abnormalities developed in childhood or later in all previously described patients. We report a more severe form ofl-2-hydroxyglutaric aciduria in which an infant presented shortly after birth with hypotonia, apnoea, and seizures, leading to death in the perinatal period. Computerized tomography scans of the brain at 1 day and 2 weeks of age showed abnormal low density of the cerebellum. Examination of the brain showed brainstem and cerebellar atrophy with neuronal loss and gliosis in an olivopontocerebellar distribution. The diagnosis ofl-2-hydroxyglutaric aciduria should be considered in any non-dysmorphic newborn with progressive neurological abnormalities and CNS imaging suggesting low density and size of the cerebellum. The diagnostic consideration is based initially on clinical findings. Conventional urine organic acid analysis reveals the presence of 2-hydroxyglutaric aciduria. Specific diagnosis requires methodologies which distinguish thel- from thed-isomer.

3D global and regional patterns of human fetal subplate growth determined in utero.

The waiting period of subplate evolution is a critical phase for the proper formation of neural connections in the brain. During this time, which corresponds to 15 to 24xa0postconceptual weeks (PCW) in the human fetus, thalamocortical and cortico-cortical afferents wait in and are in part guided by molecules embedded in the extracellular matrix of the subplate. Recent advances in fetal MRI techniques now allow us to study the developing brain anatomy in 3D from in utero imaging. We describe a reliable segmentation protocol to delineate the boundaries of the subplate from T2-W MRI. The reliability of the protocol was evaluated in terms of intra-rater reproducibility on a subset of the subjects. We also present the first 3D quantitative analyses of temporal changes in subplate volume, thickness, and contrast from 18 to 24xa0PCW. Our analysis shows that firstly, global subplate volume increases in proportion with the supratentorial volume; the subplate remained approximately one-third of supratentorial volume. Secondly, we found both global and regional growth in subplate thickness and a linear increase in the median and maximum subplate thickness through the waiting period. Furthermore, we found that posterior regions—specifically the occipital pole, ventral occipito-temporal region, and planum temporale—of the developing brain underwent the most statistically significant increases in subplate thickness. During this period, the thickest region was the developing somatosensory/motor cortex. The subplate growth patterns reported here may be used as a baseline for comparison to abnormal fetal brain development.