Selective Head versus Whole Body Cooling Treatment of Hypoxic-Ischemic Encephalopathy: Comparison of Electroencephalogram and Magnetic Resonance Imaging Findings.

OBJECTIVE: This study aimed to compare the utility of electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) to detect brain dysfunction and injury across a cohort of newborn infants treated with selective head cooling (SHC) or whole body cooling (WBC). STUDY DESIGN: Therapeutic hypothermia (TH) is a standard neuroprotection tool for hypoxic-ischemic encephalopathy (HIE) in neonates. Sixty-six newborns, SHC (n = 22) and WBC (n = 44), were studied utilizing standardized scoring systems for interpretation of EEG and MRI based on the severity of the findings. RESULTS: SHC- and WBC-treated groups did not differ significantly amongst most of the baseline parameters. EEGs obtained postcooling were abnormal in 58 of 61 (95%) infants. The severity of the EEG background changes (depressed and undifferentiated background) was more prevalent in the SHC (8/21 [38%]) than in the WBC group (5/40 [13%]). Brain MRIs showed HIE changes in 26 of 62 (42%) newborns treated with TH. MRI abnormalities of basal ganglia, thalamic, and parenchymal lesions were more common in the SHC (5/19) versus the WBC group (3/43); p = 0.04. CONCLUSION: EEG abnormalities and MRI findings of HIE were more prevalent in the SHC than in the WBC group. WBC may offer better or at least similar neuroprotection to infants with HIE.

CT of the Neck: Image Analysis and Reporting in the Emergency Setting.

Interpreting findings seen at CT of the neck is challenging owing to the complex and nuanced anatomy of the neck, which contains multiple organ systems in a relatively small area. In the emergency department setting, CT is performed to investigate acute infectious or inflammatory symptoms and chronic processes. With few exceptions, neck CT should be performed with intravenous contrast material, which accentuates abnormally enhancing phlegmonous and neoplastic tissues and can be used to delineate any abscesses or necrotic areas. As part of the evaluation, the vascular structures and aerodigestive tract must be scrutinized, particularly for patency. Furthermore, although the patient may present because of symptoms that suggest non-life-threatening conditions involving structures such as the teeth or salivary glands, there may be serious implications for other areas, such as the orbits, brain, and spinal cord, that also may be revealed at the examination. With a focus on the emergency setting, the authors propose using an approach to interpreting neck CT findings whereby 12 areas are systematically evaluated and reported on: the cutaneous and subcutaneous soft tissues, aerodigestive tract and adjacent soft tissues, teeth and periodontal tissues, thyroid gland, salivary glands, lymph nodes, vascular structures, bony airspaces, cervical spine, orbits and imaged brain, lung apices, and superior mediastinum. The use of a systematic approach to interpreting neck CT findings is essential for identifying all salient findings, recognizing and synthesizing the implications of these findings to formulate the correct diagnosis, and reporting the findings and impressions in a complete, clear, and logical manner.Online supplemental material is available for this article.©RSNA, 2019.

Incidence and Outcomes of Pituitary Microadenomas in Children with Short Stature/Growth Hormone Deficiency.

BACKGROUND/AIMS: Patients with short stature (SS)/growth hormone deficiency (GHD) and precocious puberty (PP) undergo brain MRI to evaluate for structural brain abnormalities or pituitary lesions, and pituitary microadenomas are a common finding. Theoretically, a mass effect from these lesions could cause GHD and growth hormone treatment could cause them to enlarge, but they should not cause PP, at least in females. METHODS: We investigated if pituitary microadenomas cause GHD by comparing their incidence in patients with SS/GHD to that in females with PP. We performed a retrospective chart review of patients with these disorders who had a brain MRI between 2000 and 2013. RESULTS: The incidence of microadenoma was high in both groups, 18.5% for SS (n = 346) and 21.1% for PP females (n = 194), but did not differ between groups (p = 0.46). In patients with microadenomas, repeat imaging showed resolution in 58% (SS, n = 33) and 67% (PP females, n = 21). Importantly, none of the lesions grew, even in patients treated with growth hormone. CONCLUSIONS: Pituitary microadenomas are common in children with GHD/SS and PP, but it does not appear that they are a cause of GHD. They appear to be of limited clinical significance and should not be considered a contraindication to growth hormone therapy.

MRI Differences Associated with Intrauterine Growth Restriction in Preterm Infants.

BACKGROUND: Preterm infants are at risk for neurodevelopmental impairment. Intrauterine growth restriction (IUGR) further increases this risk. Brain imaging studies are often utilized at or near term-equivalent age to determine later prognosis. OBJECTIVE: To evaluate the association between intrauterine growth and regional brain volume on MRI scans performed in preterm infants at or near term-equivalent age. METHODS: This is a retrospective case-control study of 24 infants born at gestational age ≤30 weeks and cared for in a large, inner-city, academic neonatal intensive-care unit from 2012 to 2013. Each IUGR infant was matched with 1-2 appropriate for gestational age (AGA) infants who served as controls. Predischarge MRI scans routinely obtained at ≥36 weeks' adjusted age were analyzed for regional brain volumetric differences. We examined the association between IUGR and thalamic, basal ganglion, and cerebellar brain volumes in these preterm infants. RESULTS: Compared to AGA infants, IUGR infants had a smaller thalamus (7.88 vs. 5.87 mL, p = 0.001) and basal ganglion (8.87 vs. 6.92 mL, p = 0.002) volumes. There was no difference in cerebellar volumes between the two study groups. Linear regression analyses revealed similar trends in the associations between IUGR and brain volumes after adjusting for sex, gestational age at birth, and postconceptual age and weight at MRI. CONCLUSIONS: Thalamus and basal ganglion volumes are reduced in growth-restricted preterm infants. These differences may preferentially impact neurodevelopmental outcomes. Further research is needed to explore these relationships.

Three-dimensional ultrasound of the neonatal brain: technical approach and spectrum of disease.

Brain pathology is an important cause of morbidity and mortality in neonates, especially in the premature population. While conventional two-dimensional neurosonography is traditionally used for screening, diagnosis and monitoring of brain disorders such as germinal matrix hemorrhage, periventricular leukomalacia and hydrocephalus, three-dimensional ultrasonography has gained popularity in a variety of clinical applications in recent years. Three-dimensional ultrasonography is not yet widely utilized in pediatric imaging but is a potentially powerful tool for evaluating the neonatal brain. Three-dimensional neurosonography allows imaging of the entire brain in a single volumetric sweep and offers the capability of reconstructing images in the axial plane and performing volumetric analyses that are unavailable in conventional two-dimensional neurosonography. The purpose of this article is two-fold: (1) to present the technical aspects of three-dimensional neurosonography and (2) to illustrate the potential applications of three-dimensional neurosonography in the context of commonly encountered neonatal neuropathology.

Prenatally Diagnosed Aggressive Intracranial Immature Teratoma-Clinicopathological Correlation.

OBJECTIVE: To describe clinicopathological correlation of congenital intracranial immature teratoma. METHODS: A retrospective case analysis from a tertiary medical center. RESULTS: We report a case of an intracranial immature teratoma detected prenatally at 35 weeks of gestation. The tumor showed rapid growth, causing acute hydrocephalus requiring subsequent ventriculoperitoneal shunting. Resective surgery was performed within 2 weeks after birth. The infant died at day of life 29. Histological examination revealed an immature teratoma, with high MIB1/Ki-67 proliferation index. CONCLUSION/IMPLICATIONS: Intracranial immature teratoma with high MIB1/Ki-67 proliferation index may serve as an independent poor prognostic factor.

Association between malignancy and non-alcoholic Wernicke's encephalopathy: a case report and literature review.

BACKGROUND: Wernicke's encephalopathy is a serious medical condition associated with high morbidity and mortality caused by deficiency of thiamine. This disease is classically associated with alcoholism, but is underappreciated in the nonalcoholic population. There is growing acknowledgement of the development of Wernicke's encephalopathy in patients with malignancies. METHODS: We conducted a literature review in PubMed for cases of Wernicke's encephalopathy occurring in patients with malignancy. We also present the case of a 47-year-old woman with recurrent laryngeal cancer and multiple hospital admissions for malnutrition. Neurological examination was notable for pendular nystagmus, severe gait ataxia, confusion, and poor memory consolidation. MRI of the brain was significant for T2-weighted fluid-attenuated inversion recovery hyperintensities in periaqueductal regions, medial thalami, and the tectal plate, typical for Wernicke's encephalopathy. She was treated with thiamine repletion, and had marked improvement in her mental status and some improvement in her vision problems and ataxia, although some nystagmus and significant short-term memory impairment persisted. RESULTS: The literature review yielded dozens of case reports of Wernicke's encephalopathy in patients with malignancy, dominated by cases of patients with malignancies of the gastrointestinal system, followed by those with hematologic malignancies. CONCLUSIONS: Malignancy is an important risk factor for the development of Wernicke's encephalopathy. This diagnosis is underappreciated and difficult for the clinician to discern from multifactorial delirium. Clinicians should be aware to treat at-risk patients with thiamine immediately, especially if multiple risk factors are present.

Hippocampal sclerosis after febrile status epilepticus: the FEBSTAT study.

OBJECTIVE: Whether febrile status epilepticus (FSE) produces hippocampal sclerosis (HS) and temporal lobe epilepsy (TLE) has long been debated. Our objective is to determine whether FSE produces acute hippocampal injury that evolves to HS. METHODS: FEBSTAT and 2 affiliated studies prospectively recruited 226 children aged 1 month to 6 years with FSE and controls with simple febrile seizures. All had acute magnetic resonance imaging (MRI), and follow-up MRI was obtained approximately 1 year later in the majority. Visual interpretation by 2 neuroradiologists informed only of subject age was augmented by hippocampal volumetrics, analysis of the intrahippocampal distribution of T2 signal, and apparent diffusion coefficients. RESULTS: Hippocampal T2 hyperintensity, maximum in Sommer's sector, occurred acutely after FSE in 22 of 226 children in association with increased volume. Follow-up MRI obtained on 14 of the 22 with acute T2 hyperintensity showed HS in 10 and reduced hippocampal volume in 12. In contrast, follow-up of 116 children without acute hyperintensity showed abnormal T2 signal in only 1 (following another episode of FSE). Furthermore, compared to controls with simple febrile seizures, FSE subjects with normal acute MRI had abnormally low right to left hippocampal volume ratios, smaller hippocampi initially, and reduced hippocampal growth. INTERPRETATION: Hippocampal T2 hyperintensity after FSE represents acute injury often evolving to a radiological appearance of HS after 1 year. Furthermore, impaired growth of normal-appearing hippocampi after FSE suggests subtle injury even in the absence of T2 hyperintensity. Longer follow-up is needed to determine the relationship of these findings to TLE.

Prospects for imaging-related biomarkers of human epileptogenesis: a critical review.

To facilitate the study of epileptogenesis in humans, noninvasive biomarkers of epileptogenesis are required. No validated biomarker is currently available, but brain imaging techniques provide many attractive candidates. In this article we examine the imaging features of temporal lobe epilepsy, focusing on those that may precede the onset of epilepsy and correlate with epileptogenesis. Hippocampal volumetry and T(2) relaxometry are proposed as candidate biomarkers of epileptogenesis in temporal lobe epilepsy following febrile status epilepticus. Preliminary data suggest that these have promise, and the ongoing Consequences of Prolonged Febrile Seizures in Childhood (FEBSTAT) study will provide more conclusive evidence as to their validity. At this time there are no other clear candidates for imaging-related biomarkers of epileptogenesis in human studies.

Cranial nerve involvement with juvenile polyarteritis nodosa: clinical manifestations and treatment.

Juvenile polyarteritis nodosa, a rare systemic vasculitis, may present with a wide variety of clinical manifestations. Neurologic involvement has been reported in as high as 50% to 70% of patients; however, the incidence of cranial nerve palsies is extremely uncommon. We report here the case of a 20-month-old girl with juvenile polyarteritis nodosa who developed cranial nerve III palsy, demonstrated both clinically and radiographically on MRI despite aggressive management with immunosuppressants. Neurologic manifestations resolved with treatment including corticosteroids and cyclophosphamide; however, persistent fevers, rash, and headaches interfered with attempts at a corticosteroid taper. Subsequent therapy with a combination of mycophenolate mofetil and infliximab proved highly efficacious in inducing disease remission and eventual discontinuation of corticosteroids. Knowledge about the management of refractory juvenile polyarteritis nodosa is limited. Here we report a rare case of cranial nerve involvement, as demonstrated on MRI, and successful management with a regimen of mycophenolate mofetil and infliximab.

The neuroradiological findings in a case of Revesz syndrome.

Revesz syndrome is a variant of dyskeratosis congenita characterized by aplastic anemia, retinopathy, and central nervous system abnormalities. We describe a 3-year-old boy in whom the spectrum of neuroimaging findings, including intracranial calcifications, cerebellar hypoplasia and unusual brain lesions were found by biopsy to be gliosis despite their enhancement and progression. In patients with dyskeratosis-related syndromes, non-neoplastic parenchymal brain lesions occur and gliosis should be considered in the differential diagnosis for progressive enhancing brain lesions. Should this finding be confirmed consistently in additional cases, brain biopsy could potentially be avoided.

Transgenic mice overexpressing BMP4 develop a fibrodysplasia ossificans progressiva (FOP)-like phenotype.

Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary connective tissue disease characterized by progressive postnatal heterotopic bone formation. Although the genetic defects of FOP are not known, several lines of evidence have suggested that bone morphogenetic protein-4 (BMP4) may be involved in the pathophysiology. Nevertheless BMP4-transgenic mice have previously failed to develop the disorder and there has been no good animal model of the disease. Here, we report that a unique transgenic mouse line that overexpresses BMP4 under control of the neuron-specific enolase (NSE) promoter develops a FOP-like phenotype. Mating of these animals with transgenic animals that overexpress the BMP inhibitor noggin prevents the disorder, confirming the role of BMP4 in the pathogenesis of the disease. Heterotopic bone formation in these animals appears to follow the classic endochondral ossification pathway. Sex-mismatched cell transplantation experiments indicate that multiple cell sources contribute to the heterotopic ossification. This remarkable animal model provides a unique opportunity to further study the role of the BMP signaling pathway in heterotopic ossification and to improve our understanding of the clinical aspects of FOP.

Target-derived BMP signaling limits sensory neuron number and the extent of peripheral innervation in vivo.

The role of target-derived BMP signaling in development of sensory ganglia and the sensory innervation of the skin was examined in transgenic animals that overexpress either the BMP inhibitor noggin or BMP4 under the control of a keratin 14 (K14) promoter. Overexpression of noggin resulted in a significant increase in the number of neurons in the trigeminal and dorsal root ganglia. Conversely, overexpression of BMP4 resulted in a significant decrease in the number of dorsal root ganglion neurons. There was no significant change in proliferation of trigeminal ganglion neurons in the noggin transgenic animals, and neuron numbers did not undergo the normal developmental decrease between E12.5 and the adult, suggesting that programmed cell death was decreased in these animals. The increase in neuron numbers in the K14-noggin animals was followed by an extraordinary increase in the density of innervation in the skin and a marked change in the pattern of innervation by different types of fibers. Conversely, the density of innervation of the skin was decreased in the BMP4 overexpressing animals. Further Merkel cells and their innervation were increased in the K14-noggin mice and decreased in the K14-BMP4 mice. The changes in neuron numbers and the density of innervation were not accompanied by a change in the levels of neurotrophins in the skin. These findings indicate that the normal developmental decrease in neuron numbers in sensory ganglia depends upon BMP signaling, and that BMPs may limit both the final neuron number in sensory ganglia as well as the extent of innervation of targets. Coupled with prior observations, this suggests that BMP signaling may regulate the acquisition of dependence of neurons on neurotrophins for survival, as well as their dependence on target-derived neurotrophins for determining the density of innervation of the target.

Transgenic overexpression of BMP4 increases astroglial and decreases oligodendroglial lineage commitment.

Bone morphogenetic proteins (BMPs) promote astrocytic differentiation of cultured subventricular zone stem cells. To determine whether BMPs regulate the astrocytic lineage in vivo, transgenic mice were constructed that overexpress BMP4 under control of the neuron-specific enolase (NSE) promoter. Overexpression of BMP4 was first detectable by Western analysis on embryonic day 16 and persisted into the adult. The overexpression of BMP4 resulted in a remarkable 40% increase in the density of astrocytes in multiple brain regions accompanied by a decrease in the density of oligodendrocytes ranging between 11 and 26%, depending on the brain region and the developmental stage. No changes in neuron numbers or the pattern of myelination were detected, and there were no gross structural abnormalities. Similar phenotypes were observed in three independently derived transgenic lines. Coculture of transgenic neurons with neural progenitor cells significantly enhanced astrocytic lineage commitment by the progenitors; this effect was blocked by the BMP inhibitor Noggin, indicating that the stimulation of astrogliogenesis was due to BMP4 release by the transgenic neurons. These observations suggest that BMP4 directs progenitor cells in vivo to commit to the astrocytic rather than the oligodendroglial lineage. Further, differentiation of radial glial cells into astrocytes was accelerated, suggesting that radial glia were a source of at least some of the supernumerary astrocytes. Therefore, BMPs are likely important mediators of astrocyte development in vivo.

In vivo evidence that BMP signaling is necessary for apoptosis in the mouse limb.

To determine the role of Bone morphogenetic protein (BMP) signaling in murine limb development in vivo, the keratin 14 promoter was used to drive expression of the BMP antagonist Noggin in transgenic mice. Phosphorylation and nuclear translocation of Smad1/5 were dramatically reduced in limbs of the transgenic animals, confirming the inhibition of BMP signaling. These mice developed extensive limb soft tissue syndactyly and postaxial polydactyly. Apoptosis in the developing limb necrotic zones was reduced with incomplete regression of the interdigital tissue. The postaxial extra digit is also consistent with a role for BMPs in regulating apoptosis. Furthermore, there was persistent expression of Fgf8, suggesting a delay in the regression of the AER. However, Msx1 and Msx2 expression was unchanged in these transgenic mice, implying that induction of these genes is not essential for mediating BMP-induced interdigital apoptosis in mice. These abnormalities were rescued by coexpressing BMP4 under the same promoter in double transgenic mice, suggesting that the limb abnormalities are a direct effect of inhibiting BMP signaling.