Publications by authors named "David M Mirsky"

52 Publications

ACR Appropriateness Criteria® Seizures-Child.

J Am Coll Radiol 2021 May;18(5S):S199-S211

Specialty Chair, Riley Hospital for Children Indiana University, Indianapolis, Indiana.

In children, seizures represent an extremely heterogeneous group of medical conditions ranging from benign cases, such as a simple febrile seizure, to life-threatening situations, such as status epilepticus. Underlying causes of seizures also represent a wide range of pathologies from idiopathic cases, usually genetic, to a variety of acute and chronic intracranial or systemic abnormalities. This document discusses appropriate utilization of neuroimaging tests in a child with seizures. The clinical scenarios in this document take into consideration different circumstances at the time of a child's presentation including the patient's age, precipitating event (if any), and clinical and electroencephalogram findings and include neonatal seizures, simple and complex febrile seizures, post-traumatic seizures, focal seizures, primary generalized seizures in a neurologically normal child, and generalized seizures in neurologically abnormal child. This practical approach aims to guide clinicians in clinical decision-making and to help identify efficient and appropriate imaging workup. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
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http://dx.doi.org/10.1016/j.jacr.2021.02.020DOI Listing
May 2021

Neuroimaging of retinal hemorrhage utilizing adjunct orbital susceptibility-weighted imaging.

Pediatr Radiol 2021 May 12;51(6):991-996. Epub 2021 Mar 12.

Division of Pediatric Ophthalmology, Strabismus, and Adult Motility, Eye Center, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.

Retinal hemorrhages are an integral part of the evaluation of abusive head trauma (AHT). Timely detection of retinal hemorrhage not only facilitates the diagnosis of AHT, but has the potential to prevent further abuse to the child and the siblings and to identify the abuser. The gold standard for diagnosing retinal hemorrhage is a dilated fundoscopy exam, which requires pharmacological dilation. As such, there is a small percentage of patients for whom the dilated fundoscopy exam might be delayed. Evolving literature suggests that MRI, specifically susceptibility-weighted imaging (SWI), of the orbits might provide an alternative diagnostic tool for noninvasively detecting retinal hemorrhages, particularly when there is a delay in administering the dilated fundoscopy exam. In this paper we review the utility of SWI for detecting retinal hemorrhages in abusive head trauma, including discussion of diagnostic limitations and future research.
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http://dx.doi.org/10.1007/s00247-020-04897-6DOI Listing
May 2021

Visualization of the fetal anus by prenatal ultrasound for the diagnosis of anorectal malformations: is it feasible?

Pediatr Surg Int 2021 Apr 5;37(4):425-430. Epub 2021 Jan 5.

University of Colorado School of Medicine, Aurora, USA.

Purpose: The goal of this study was to determine the feasibility of identifying the anal dimple (AD) on routine prenatal ultrasound. Using the presence, absence, appearance, and location of the anal dimple as an indirect sign for possible underlying anorectal malformations (ARM), we hypothesize that evaluation of the anal dimple as part of the fetal anatomic survey may increase the sensitivity in detecting less severe ARMs.

Methods: In a prospective longitudinal observational study, pregnant women who underwent prenatal ultrasound (US) at the Colorado Fetal Care Center between January 2019 and 2020 were enrolled. The variables recorded included gestational age, singleton versus multiple pregnancy, gender of the fetus, visualization of the AD, and reason for non-visualization of the AD.

Results: A total of 900 ultrasounds were performed, evaluating 1044 fetuses, in 372 different pregnant women. Gestational ages ranged from 16 to 38 weeks. The AD was visualized in 612 fetuses (58.6%) and not seen in 432 (41.4%). The two most common reasons for non-visualization were extremes in gestational age (n = 155; 36%) and fetal position (n = 152; 35.3%). The optimal gestational age range for AD visualization was 28-33 weeks + 6 days, with 78.1% visualization rate.

Conclusion: Visualization of the anal dimple by ultrasound is feasible and may aid in the detection of less severe ARMs, ultimately impacting pregnancy management and family counseling. The optimal timing for anal dimple visualization is late second and third trimester.
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http://dx.doi.org/10.1007/s00383-020-04840-8DOI Listing
April 2021

A novel acceptor stem variant in mitochondrial tRNA impairs mitochondrial translation and is associated with a severe phenotype.

Mol Genet Metab 2020 12 24;131(4):398-404. Epub 2020 Nov 24.

Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA; Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, 13121 East 16th Avenue, Aurora, CO, USA. Electronic address:

Genetic defects in mitochondrial DNA encoded tRNA genes impair mitochondrial translation with resultant defects in the mitochondrial respiratory chain and oxidative phosphorylation system. The phenotypic spectrum of disease seen in mitochondrial tRNA defects is variable and proving pathogenicity of new variants is challenging. Only three pathogenic variants have been described previously in the mitochondrial tRNA gene MT-TY, with the reported phenotypes consisting largely of adult onset myopathy and ptosis. We report a patient with a novel MT-TY acceptor stem variant m.5889A>G at high heteroplasmy in muscle, low in blood, and absent in the mother's blood. The phenotype consisted of a childhood-onset severe multi-system disorder characterized by a neurodegenerative course including ataxia and seizures, failure-to-thrive, combined myopathy and neuropathy, and hearing and vision loss. Brain imaging showed progressive atrophy and basal ganglia calcifications. Mitochondrial biomarkers lactate and GDF15 were increased. Functional studies showed a deficient activity of the respiratory chain enzyme complexes containing mtDNA-encoded subunits I, III and IV. There were decreased steady state levels of these mitochondrial complex proteins, and presence of incompletely assembled complex V forms in muscle. These changes are typical of a mitochondrial translational defect. These data support the pathogenicity of this novel variant. Careful review of variants in MT-TY additionally identified two other pathogenic variants, one likely pathogenic variant, nine variants of unknown significance, five likely benign and four benign variants.
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http://dx.doi.org/10.1016/j.ymgme.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749820PMC
December 2020

Imaging of fetal ventriculomegaly.

Pediatr Radiol 2020 12 30;50(13):1948-1958. Epub 2020 Nov 30.

Department of Radiology, Children's Hospital Colorado, University of Colorado School of Medicine, 13123 East 16th Ave., Box B125, Aurora, CO, 80045, USA.

Fetal ventriculomegaly is the most common central nervous system abnormality detected by prenatal imaging. It has a high association with other anomalies. Etiologies and prognoses for fetal ventriculomegaly range from normal outcomes to significant neurodevelopmental sequelae. In this paper, we review the development, terminology, pathogenesis, imaging and prognosis of fetal ventriculomegaly.
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http://dx.doi.org/10.1007/s00247-020-04880-1DOI Listing
December 2020

How to read a fetal magnetic resonance image 101.

Pediatr Radiol 2020 12 30;50(13):1810-1829. Epub 2020 Nov 30.

Radiology Department, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA, 10104, USA.

Accurate antenatal diagnosis is essential for planning appropriate pregnancy management and improving perinatal outcomes. The provision of information vital for prognostication is a crucial component of prenatal imaging, and this can be enhanced by the use of fetal MRI. Image acquisition, interpretation and reporting of a fetal MR study can be daunting to the individual who has encountered few or none of these examinations. This article provides the radiology trainee with a general approach to interpreting a fetal MRI. The authors review the added value of prenatal MRI in the overall assessment of fetal wellbeing, discuss MRI protocols and techniques, and review the normal appearance of maternal and fetal anatomy. The paper concludes with a sample template for structured reporting, to serve as a checklist and guideline for reporting radiologists.
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http://dx.doi.org/10.1007/s00247-020-04768-0DOI Listing
December 2020

Robust deep learning classification of adamantinomatous craniopharyngioma from limited preoperative radiographic images.

Sci Rep 2020 10 9;10(1):16885. Epub 2020 Oct 9.

Division of Pediatric Neurosurgery, Children's Hospital Colorado, Aurora, 80045, USA.

Deep learning (DL) is a widely applied mathematical modeling technique. Classically, DL models utilize large volumes of training data, which are not available in many healthcare contexts. For patients with brain tumors, non-invasive diagnosis would represent a substantial clinical advance, potentially sparing patients from the risks associated with surgical intervention on the brain. Such an approach will depend upon highly accurate models built using the limited datasets that are available. Herein, we present a novel genetic algorithm (GA) that identifies optimal architecture parameters using feature embeddings from state-of-the-art image classification networks to identify the pediatric brain tumor, adamantinomatous craniopharyngioma (ACP). We optimized classification models for preoperative Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and combined CT and MRI datasets with demonstrated test accuracies of 85.3%, 83.3%, and 87.8%, respectively. Notably, our GA improved baseline model performance by up to 38%. This work advances DL and its applications within healthcare by identifying optimized networks in small-scale data contexts. The proposed system is easily implementable and scalable for non-invasive computer-aided diagnosis, even for uncommon diseases.
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http://dx.doi.org/10.1038/s41598-020-73278-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547020PMC
October 2020

"Growing cerebellum" requiring operative decompression following perinatal ventriculoperitoneal shunting.

Childs Nerv Syst 2021 Jan 22;37(1):13-19. Epub 2020 Sep 22.

Department of Pediatric Neurosurgery, Children's Hospital Colorado, University of Colorado School of Medicine, 13123 E 16th Ave, Aurora, CO, 80045, USA.

Introduction: While cases of acquired Chiari I malformation following ventriculoperitoneal shunting for posthemorrhagic hydrocephalus have been reported, true disproportionate cerebellar growth is rare, with no previous cases requiring posterior fossa decompression reported.

Clinical Presentation: We present a premature neonate who underwent ventriculoperitoneal shunt placement for suspected posthemorrhagic hydrocephalus. He subsequently developed a symptomatic Chiari I malformation with volumetric measurements demonstrating disproportionate growth of the cerebellum. He did not demonstrate thickening of the supratentorial or posterior fossa cranium. The patient underwent an extradural posterior fossa decompression, with resolution of symptoms.

Outcome And Conclusions: We review the extant literature regarding the development of Chiari malformation type I as a manifestation of craniocerebral disproportion (CCD) following shunt placement for posthemorrhagic hydrocephalus of prematurity. Most previous reports reflect a mechanism that includes underdevelopment of the intracranial posterior fossa (or supratentorial) volume. The case presented in this report, as well as one additional case, indicates that there may exist a variant mechanism, characterized by rapid growth of the cerebellum itself, in the absence of one of the rare syndromes associated with primary macrocerebellum. While this case was effectively managed with extradural posterior fossa decompression, previous reports indicate that supratentorial cranial expansion procedures are preferable in some cases. As such, pediatric neurosurgeons should be able to distinguish the patterns of craniocerebral disproportion when considering treatment options for these patients. Further investigation regarding these uncommon patients may better describe the underlying mechanisms.
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http://dx.doi.org/10.1007/s00381-020-04864-4DOI Listing
January 2021

The mitochondrial DNA variant m.9032T > C in MT-ATP6 encoding p.(Leu169Pro) causes a complex mitochondrial neurological syndrome.

Mitochondrion 2020 11 12;55:8-13. Epub 2020 Sep 12.

Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA; Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, 13121 East 16th Avenue, Aurora, CO, USA. Electronic address:

Diagnosing complex V deficiencies caused by new variants in mitochondrial DNA is challenging due to the rarity, phenotypic diversity, and limited functional assessments. We describe a child with the m.9032T > C variant in MT-ATP6 encoding p.(Leu169Pro), with primary presentation of microcephaly, ataxia, hearing loss, and lactic acidosis. Functional studies reveal abnormal fragment F of complex V on blue native gel electrophoresis. Respirometry showed excessively tight coupling through complex V depressing oxygen consumption upon ADP stimulation and an excessive increase following uncoupling, in the presence of upregulation of mitochondrial biogenesis. These data add evidence about pathogenicity and functional impact of this variant.
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http://dx.doi.org/10.1016/j.mito.2020.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669648PMC
November 2020

ddPCR Analysis Reveals BRAF V600E Mutations Are Infrequent in Isolated Pituitary Langerhans Cell Histiocytosis Patients.

J Neuropathol Exp Neurol 2020 12;79(12):1313-1319

Morgan Adams Foundation Pediatric Brain Tumor Research Program, Center for Cancer and Blood Disorders, Children's Hospital Colorado.

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a highly variable clinical presentation affecting people of all ages. Mutations in BRAF V600E are the most identifiable molecular alteration in LCH although its incidence in pediatric patients with isolated pituitary stalk involvement is not well described. Pediatric patients with LCH and isolated pituitary stalk involvement typically present with central diabetes insipidus. Diagnosis requires a transcranial biopsy which often yields scant tissue. We sought to determine the prevalence of BRAF V600E mutations in patients with isolated pituitary stalk LCH using digital droplet polymerase chain reaction because this method requires minimal tumor DNA. We identified 8 patients with isolated pituitary stalk thickening who underwent a biopsy at Children's Hospital Colorado from January 2001 to December 2019, as well as 6 patients with systemic LCH diagnosed by biopsy in the same period as a comparison. Only one out of the 8 patients with isolated thickened pituitary stalk was found to have a detectable BRAF V600E mutation. Five out of the 6 patients with systemic LCH had a detectable BRAF V600E mutation. In our series, BRAF V600E mutations are rare in pediatric patients with LCH and isolated pituitary stalk involvement.
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http://dx.doi.org/10.1093/jnen/nlaa091DOI Listing
December 2020

ACR Appropriateness Criteria® Cerebrovascular Disease-Child.

J Am Coll Radiol 2020 May;17(5S):S36-S54

Specialty Chair, Riley Hospital for Children Indiana University, Indianapolis, Indiana.

Stroke is an uncommon but an important and under-recognized cause of morbidity and mortality in children. Strokes may be due to either brain ischemia or intracranial hemorrhage. Common symptoms of pediatric acute stroke include headache, vomiting, focal weakness, numbness, visual disturbance, seizures, and altered consciousness. Most children presenting with an acute neurologic deficit do not have an acute stroke, but have symptoms due to stroke mimics which include complicated migraine, seizures with postictal paralysis, and Bell palsy. Because of frequency of stroke mimics, in children and the common lack of specificity in symptoms, the diagnosis of a true stroke may be delayed. There are a relatively large number of potential causes of stroke mimic and true stroke. Consequently, imaging plays a critical role in the assessment of children with possible stroke and especially in children who present with acute onset of stroke symptoms. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
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http://dx.doi.org/10.1016/j.jacr.2020.01.036DOI Listing
May 2020

ACR Appropriateness Criteria® Head Trauma-Child.

J Am Coll Radiol 2020 May;17(5S):S125-S137

Specialty Chair, Riley Hospital for Children Indiana University, Indianapolis, Indiana.

Head trauma is a frequent indication for cranial imaging in children. The majority of accidental pediatric head trauma is minor and sustained without intracranial injury. Well-validated pediatric-specific clinical decision guidelines should be used to identify very low-risk children who can safely forgo imaging. In those who require acute imaging, CT is considered the first-line imaging modality for suspected intracranial injury because of the short duration of the examination and its high sensitivity for acute hemorrhage. MRI can accurately detect traumatic complications, but often necessitates sedation in children, owing to the examination length and motion sensitivity, which limits rapid assessment. There is a paucity of literature regarding vascular injuries in pediatric blunt head trauma and imaging is typically guided by clinical suspicion. Advanced imaging techniques have the potential to identify changes that are not seen by standard imaging, but data are currently insufficient to support routine clinical use. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
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http://dx.doi.org/10.1016/j.jacr.2020.01.026DOI Listing
May 2020

COVID-19: A primer for Neuroradiologists.

Neuroradiology 2020 Jun;62(6):647-648

Head, Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

The potential for central nervous system (CNS) involvement in coronavirus disease 2019 (COVID-19) is a matter of grave concern and there is a relevant body of evidence in the basic sciences to support this possibility. A neuroradiologist should be aware of the potential mechanisms involved in the neuropathogenesis of this virus, as we begin to see cases with abnormal brain scans emerging from all parts of the world.
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http://dx.doi.org/10.1007/s00234-020-02437-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186113PMC
June 2020

Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease.

J Inherit Metab Dis 2020 09 15;43(5):1024-1036. Epub 2020 Apr 15.

Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, Colorado.

Hydrogen sulfide, a signaling molecule formed mainly from cysteine, is catabolized by sulfide:quinone oxidoreductase (gene SQOR). Toxic hydrogen sulfide exposure inhibits complex IV. We describe children of two families with pathogenic variants in SQOR. Exome sequencing identified variants; SQOR enzyme activity was measured spectrophotometrically, protein levels evaluated by western blotting, and mitochondrial function was assayed. In family A, following a brief illness, a 4-year-old girl presented comatose with lactic acidosis and multiorgan failure. After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging. She died shortly after. Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex. Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation. Both patients were homozygous for c.637G > A, which we identified as a founder mutation in the Lehrerleut Hutterite with a carrier frequency of 1 in 13. The resulting p.Glu213Lys change disrupts hydrogen bonding with neighboring residues, resulting in severely reduced SQOR protein and enzyme activity, whereas sulfide generating enzyme levels were unchanged. In family B, a boy had episodes of encephalopathy and basal ganglia lesions. He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels. SQOR dysfunction can result in hydrogen sulfide accumulation, which, consistent with its known toxicity, inhibits complex IV resulting in energy failure. In conclusion, SQOR deficiency represents a new, potentially treatable, cause of Leigh disease.
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http://dx.doi.org/10.1002/jimd.12232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484123PMC
September 2020

Utility of image fusion software in identifying shunt malfunction.

Childs Nerv Syst 2020 04 18;36(4):749-754. Epub 2020 Jan 18.

Department of Radiology, Children's Hospital Colorado, University of Colorado Denver, Aurora, CO, USA.

Purpose: Pediatric shunt malfunction occurs frequently and is important to recognize due to the high associated morbidity and mortality. Although neuroimaging plays a crucial role in the diagnosis, it remains imperfect. We sought to identify the effect of image fusion software in predicting shunt malfunction.

Methods: A total of 248 rapid shunt series brain MRIs performed between 2013 and 2017 were compared with prior neuroimaging for changes in ventricular size by two methods: radiology report and Brainlab fusion. Shunt malfunction was defined by an operative report confirming malfunction within 72 h of neuroimaging. The two methods were compared by logistic regression models, with sensitivity and specificity subsequently calculated.

Results: Shunt malfunction was identified in 40 cases (16.1%). Imaging report demonstrated a lower Akaike information criterion than the Brainlab fusion and is therefore a better fitting model. While sensitivity is similar for the two models, 0.94 (0.90 to 0.97, 95% CI) for imaging report, and 0.95 (0.91 to 0.98, 95% CI) for Brainlab, the specificity was significantly different, 0.50 (0.37 to 0.63, 95% CI) and 0.33 (0.24 to 0.44, 95% CI) respectively.

Conclusions: Our data indicate that an increased ability to detect subtle changes in ventricular size does not translate to improved accuracy, but instead leads to decreased specificity, and therefore an overdiagnosis of shunt malfunction in children with normally functioning shunts. While imaging continues to play a prominent role in the identification of shunt malfunction, neurosurgical clinical evaluation remains crucial to the final diagnosis.
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http://dx.doi.org/10.1007/s00381-019-04385-9DOI Listing
April 2020

The utility of magnetic resonance imaging in pediatric trauma patients suspected of having cervical spine injuries.

J Trauma Acute Care Surg 2019 12;87(6):1328-1335

From the Department of Pediatric Surgery (S.C.D.); Department of Pediatric Neurosurgery (K.G., S.G., T.C.H., N.H., A.A., B.R.O., C.C.W., M.H.H.); Department of Radiology (D.M.M., N.V.S.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado.

Background: Pediatric cervical spine injuries (CSI) are rare but potentially devastating sequelae of blunt trauma. Existing protocols to evaluate children at risk for CSI frequently incorporate computed topography (CT) and magnetic resonance imaging (MRI); however, the clinical value of performing both remains unclear.

Methods: Single-center retrospective review of pediatric trauma patients who underwent both CT and MRI of the cervical spine between 2001 and 2015. Based on radiographic findings, CT and MRI results were grouped into one of three categories: no injury, stable injury, or unstable injury. Radiographic instability was defined by disruption of two or more contiguous spinal columns while radiographic stability was defined by any other acute cervical spine abnormality on imaging. Clinical instability was defined by the need for surgical intervention (halo or spinal fusion), with the remaining patients, including children discharged in a cervical collar, considered clinically stable.

Results: In total, 221 children met inclusion criteria, with a median age of 9 (interquartile range, 3-14). The Glasgow Coma Scale (GCS) score of the cohort was 9 (interquartile range, 4-15). Thirty-three (14.9%) children had clinically unstable injuries, requiring surgical intervention. Among the 160 (72.4%) children with no injury on CT, MRI identified no injury in 84 (52.5%) cases, a stable injury in 76 (47.5%) cases, and an unstable injury in none. Among the 21 children with stable injuries on CT, MRI findings were concordant in 17 (81.0%) cases. In four (19.0%) cases, a spinal column injury was identified on CT and appeared to be stable, but later deemed unstable on MRI. Forty (18.1%) patients had an unstable injury on CT with 100% MRI concordance.

Conclusion: In pediatric trauma patients suspected of having a CSI, a normal cervical spine CT is sufficient to rule out a clinically significant CSI as no child with a normal cervical CT was found to be radiographically or clinically unstable.

Level Of Evidence: Diagnostic Test, level III.
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http://dx.doi.org/10.1097/TA.0000000000002487DOI Listing
December 2019

Subpial Hemorrhage of the Neonate.

Stroke 2020 01 7;51(1):315-318. Epub 2019 Nov 7.

Department of Radiology (N.V.S., D.M.M.), Children's Hospital Colorado, Aurora.

Background and Purpose- Subpial hemorrhage of the neonate is a rare stroke subtype reported in few case series. Birth trauma and coagulopathy are commonly proposed etiologies. We evaluated our subpial hemorrhage of the neonate patient cohort to expand current understanding Methods- Cases of subpial hemorrhage of the neonate were identified by keyword searches of the institutional database. The medical records and magnetic resonance imagings were reviewed. Results- Seventeen cases were identified. Assisted delivery occurred in 12% of cases, and acute coagulation abnormalities occurred in 77%. Subpial hemorrhage of the neonate was located in the temporal lobe in 82%, with cytotoxic edema and medullary vein congestion and thrombosis subjacent to the hemorrhages in 100% and 76% of cases, respectively. Neurological disability was present in 44% of survivors. Three patients had chronic coagulation abnormalities. Conclusions- In our cohort, clinical findings supporting a potential relationship with birth trauma were infrequent. The imaging findings suggest a nonarterial, deep venous pattern of hemorrhagic ischemia.
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http://dx.doi.org/10.1161/STROKEAHA.119.025987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050827PMC
January 2020

Interrater reliability of a method to assess hypothalamic involvement in pediatric adamantinomatous craniopharyngioma.

J Neurosurg Pediatr 2019 Oct 11:1-6. Epub 2019 Oct 11.

1Department of Neurosurgery, University of Colorado, Aurora.

Objective: Pediatric adamantinomatous craniopharyngiomas (ACPs) are histologically benign brain tumors that confer significant neuroendocrine morbidity. Previous studies have demonstrated that injury to the hypothalamus is associated with worsened quality of life and a shorter lifespan. This insight helps many surgeons define the goals of surgery for patients with ACP. Puget and colleagues proposed a 3-tiered preoperative and postoperative grading system based on the degree of hypothalamic involvement identified on MRI. In a prospective cohort from their institution, the authors found that use of the system to guide operative goals was associated with decreased morbidity. To date, however, the Puget system has not been externally validated. Here, the authors present an interrater reliability study that assesses the generalizability of this system for surgeons planning initial operative intervention for children with craniopharyngiomas.

Methods: A panel of 6 experts, consisting of pediatric neurosurgeons and pediatric neuroradiologists, graded 30 preoperative and postoperative MRI scans according to the Puget system. Interrater reliability was calculated using Fleiss' κ and Krippendorff's α statistics.

Results: Interrater reliability in the preoperative context demonstrated moderate agreement (κ = 0.50, α = 0.51). Interrater reliability in the postoperative context was 0.27 for both methods of statistical evaluation.

Conclusions: Interrater reliability for the system as defined is moderate. Slight refinements of the Puget MRI grading system, such as collapsing the 3 grades into 2, may improve its reliability, making the system more generalizable.
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http://dx.doi.org/10.3171/2019.8.PEDS19295DOI Listing
October 2019

Feasibility and Accuracy of Fast MRI Versus CT for Traumatic Brain Injury in Young Children.

Pediatrics 2019 10;144(4)

School of Medicine, University of Colorado, Denver, Colorado.

Background: Computed tomography (CT) is commonly used for children when there is concern for traumatic brain injury (TBI) and is a significant source of ionizing radiation. Our objective was to determine the feasibility and accuracy of fast MRI (motion-tolerant MRI sequences performed without sedation) in young children.

Methods: In this prospective cohort study, we attempted fast MRI in children <6 years old who had head CT performed and were seen in the emergency department of a single, level 1 pediatric trauma center. Fast MRI sequences included 3T axial and sagittal T2 single-shot turbo spin echo, axial T1 turbo field echo, axial fluid-attenuated inversion recovery, axial gradient echo, and axial diffusion-weighted single-shot turbo spin echo planar imaging. Feasibility was assessed by completion rate and imaging time. Fast MRI accuracy was measured against CT findings of TBI, including skull fracture, intracranial hemorrhage, or parenchymal injury.

Results: Among 299 participants, fast MRI was available and attempted in 225 (75%) and completed in 223 (99%). Median imaging time was 59 seconds (interquartile range 52-78) for CT and 365 seconds (interquartile range 340-392) for fast MRI. TBI was identified by CT in 111 (50%) participants, including 81 skull fractures, 27 subdural hematomas, 24 subarachnoid hemorrhages, and 35 other injuries. Fast MRI identified TBI in 103 of these (sensitivity 92.8%; 95% confidence interval 86.3-96.8), missing 6 participants with isolated skull fractures and 2 with subarachnoid hemorrhage.

Conclusions: Fast MRI is feasible and accurate relative to CT in clinically stable children with concern for TBI.
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http://dx.doi.org/10.1542/peds.2019-0419DOI Listing
October 2019

Targeting IL-6 Is a Potential Treatment for Primary Cystic Craniopharyngioma.

Front Oncol 2019 21;9:791. Epub 2019 Aug 21.

Department of Pediatrics, University of Colorado Denver, Aurora, CO, United States.

Adamantinomatous craniopharyngioma (ACP) makes up between 6 and 8% of pediatric brain tumors and is the most common pediatric tumor arising in the sellar/suprasellar region of the brain. The 10-year survival for patients diagnosed with craniopharyngioma ranges between 64 and 92%, but complicating factors such as location, common cyst formation, and potential hypothalamic infiltration cause significant morbidity in this population. There are a number of therapeutic options for children with ACP, including surgery, radiation, and cyst directed therapies such as interferon and bleomycin. Research has raised concerns regarding the efficacy and side effects associated with these conventional therapies, as well as with the difficulty in treating recurrent cystic ACP. Evidence from our group and others has shown that the cystic and solid tumor components of craniopharyngioma have high levels of IL-6R and IL-6, providing a potential target for therapy. Tocilizumab, a humanized monoclonal antibody, acts against soluble and membrane bound IL-6R, and has been widely utilized in pediatric patients. Two patients with recurrent cystic ACP were offered systemically administered tocilizumab or a combination of tocilizumab and bevacizumab on a compassionate use basis. Both patients' tumors had a significant response, with decreased cyst burden, supporting the assertion that tocilizumab with or without bevacizumab may be an option for patients suffering from cystic ACP.
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http://dx.doi.org/10.3389/fonc.2019.00791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712354PMC
August 2019

Differentiating presacral masses in anorectal malformations and isolated sacrococcygeal teratomas.

Pediatr Surg Int 2019 Sep 29;35(9):979-983. Epub 2019 Jun 29.

Department of Pediatric Surgery, International Center for Colorectal and Urogenital Care, Children's Hospital Colorado, University of Colorado, 13123 East 16th Avenue, Anschutz Medical Campus, Box 323, Aurora, CO, 80045, USA.

Purpose: Presacral masses associated with anorectal malformations (ARM) are most frequently dermoid or teratomas. Sacrococcygeal teratoma (SCT), in isolation, is a different condition. There are limited data comparing the two. The aim of this study was to compare presacral masses associated with ARM and isolated SCTs.

Methods: A retrospective review was performed from 1979 to 2018. Patients with presacral masses and associated ARM (n = 39) were identified and compared to patients with isolated SCTs (n = 32).

Results: Those with presacral mass and ARM had a lower proportion of immature and mixed teratomas by pathology and a longer time to mass resection. They had higher percentages of sacral anomalies (76% versus 9%), tethered cord (50% versus 6%), and other anomalies (51% versus 9%). For long-term bowel function, patients with presacral mass and ARM were more likely to be fecally incontinent and require enemas (59% versus 11%). Regarding isolated SCTs, 4% recurred with a time to recurrence of 7 months.

Conclusions: Compared to patients with isolated SCT, patients with presacral mass and ARM had lower grade tumors. In addition, they had a higher proportion of sacral defects and other congenital defects, as well as worse bowel function outcomes.
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http://dx.doi.org/10.1007/s00383-019-04510-4DOI Listing
September 2019

ACR Appropriateness Criteria Suspected Spine Trauma-Child.

J Am Coll Radiol 2019 May;16(5S):S286-S299

Specialty Chair, Riley Hospital for Children Indiana University, Indianapolis, Indiana.

Choosing the appropriate imaging in children with accidental traumatic spine injuries can be challenging because the recommendations based on scientific evidence at this time differ from those applied in adults. This differentiation is due in part to differences in anatomy and physiology of the developing spine. This publication uses scientific evidence and a panel of pediatric experts to summarize best current imaging practices for children with accidental spine trauma. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
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http://dx.doi.org/10.1016/j.jacr.2019.02.003DOI Listing
May 2019

Dual energy head CT to maintain image quality while reducing dose in pediatric patients.

Clin Imaging 2019 May - Jun;55:83-88. Epub 2019 Feb 7.

Department of Radiology, Children's Hospital Colorado, 13123 E. 16th Ave., Box 125, Aurora, CO 80045, USA.

Aim: The aim of this study was to use dual energy CT technology to maintain or improve image quality in pediatric head CT while simultaneously reducing radiation dose.

Materials And Methods: In this retrospective study, helical head CTs performed using a standard head CT protocol were compared to studies performed with a dual energy (DE) protocol. Objective comparison was performed by measuring regions of interest in 11 areas of the brain. Subjective rating for image quality using a Likert scale, was performed by three radiologists. Radiation doses were evaluated using CT dose index and dose length product.

Results: Signal-to-noise ratio was, for the most part, not significantly different between the DE and conventional scans. Contrast-to-noise ratio was slightly lower for children over 6 year of age utilizing the dual energy protocol versus the standard protocol. Qualitatively, there was little difference in image quality in patients <6 years old, with the only significant difference in infratentorial noise. However, in patients >6 years of age, infratentorial noise, sharpness and diagnostic acceptability, as well as supratentorial sharpness were all significantly improved by DE CT technique. Radiation exposure as measured by CTDI and DLP was modestly lower with the dual energy protocol in all study populations.

Conclusion: Dual energy CT can be used clinically in pediatric patients to maintain or improve image quality while reducing radiation dose.
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http://dx.doi.org/10.1016/j.clinimag.2019.02.005DOI Listing
November 2019

Age-associated hippocampal volume changes in childhood arterial ischemic stroke.

Childs Nerv Syst 2019 02 8;35(2):295-300. Epub 2018 Dec 8.

Department of Radiology, Children's Hospital Colorado, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.

Purpose: Recent evidence suggests that recovery from secondary neurodegeneration following arterial ischemic stroke (AIS) may be related to age at injury and site of occlusion. We conducted a study of hippocampal volume (HCV) in a cohort of pediatric patients with middle cerebral artery (MCA) territory AIS to determine whether HCV would be preserved in younger children as compared to older children.

Methods: This single-center, HIPAA-compliant retrospective study was approved by the institutional review board. The medical records of 149 children treated for AIS between 2000 and 2016 were reviewed for inclusion criteria: unilateral MCA territory AIS and availability of high-resolution T1-weighted MR imaging at both acute and chronic time periods. Manual segmentation was utilized to measure stroke-side HCV, contralateral HCV, hemispheric volumes, and stroke volume on each scan. To correct for variable brain size, HCV measurements were ratio normalized. Patients were divided into two age-at-stroke groups: younger (30 days-9 years old) and older (> 9-18 years old). Analysis was performed using Fisher's test or Student's t test.

Results: The MR imaging of 19 children (9 younger, 10 older) was analyzed. At follow-up, the average stroke-side HCV increased by 10.9% in the younger group and decreased by 6.3% in the older group (P = 0.010); this between-group difference remained significant even when ratio normalized (P = 0.003). The total brain volume-adjusted acute stroke size between groups was not statistically different (P = 0.649).

Conclusions: In children with AIS, younger age is associated with the relative preservation of HCV, which could reflect differences in age-related plasticity.
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http://dx.doi.org/10.1007/s00381-018-4021-5DOI Listing
February 2019

ACR Appropriateness Criteria Sinusitis-Child.

J Am Coll Radiol 2018 Nov;15(11S):S403-S412

Specialty Chair, Riley Hospital for Children Indiana University, Indianapolis, Indiana.

Sinusitis is common in children that usually resolves spontaneously. Imaging is not part of the standard of care for initial diagnosis, however may be necessary in cases with persistent or chronic sinusitis to guide surgical intervention, or to rule out intracranial and vascular complications of sinusitis. Computed tomography (CT) and magnetic resonance imaging (MRI) are the leading imaging modalities. In this article, appropriateness in use of imaging modalities are discussed under common/clinically relevant scenarios. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
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http://dx.doi.org/10.1016/j.jacr.2018.09.029DOI Listing
November 2018

Infection of the spheno-occipital synchondrosis: A morbid complication following adenoidectomy.

Int J Pediatr Otorhinolaryngol 2018 Aug 28;111:59-62. Epub 2018 May 28.

Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO, USA; Department of Pediatric Otolaryngology, Children's Hospital Colorado, Aurora, CO, USA. Electronic address:

Two 2-year-old males presented post-operatively following adenoidectomy with persistent fever and neck stiffness. After multiple office visits, both patients were admitted and found to have a widened spheno-occipital synchondrosis and other imaging findings indicative of skull base osteomyelitis. Treatment with antibiotics allowed for recovery with good long-term outcomes. Infection involving the spheno-occiptal synchondrosis is rare and its circuitous presentation of these two children no doubt led to delayed diagnosis.
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http://dx.doi.org/10.1016/j.ijporl.2018.05.012DOI Listing
August 2018

Pediatric anosmia: A case series.

Int J Pediatr Otorhinolaryngol 2018 Jul 17;110:135-139. Epub 2018 May 17.

Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO, United States; Department of Pediatric Otolaryngology, Children's Hospital Colorado, Aurora, CO, United States. Electronic address:

Introduction: Little is known about the etiology of olfactory dysfunction in the pediatric population. The aim of this study is to characterize the etiology and clinical features of anosmia and to explore evaluation options in a pediatric population.

Methods: Olfactory dysfunction was identified at a tertiary pediatric hospital between January 2003 and October 2014 using a text-based and ICD-9 search of the electronic health record system. Clinical information gathered included history, physical examination and imaging study. A phone questionnaire was completed to determine persistence and development of other rhinologic, endocrine, or neurologic symptoms.

Results: 37 children (male/female = 17/20) with mean/median ages of 13.28/14. 19 years were identified. The distribution of etiology was: rhinologic disease (N = 16), congenital (N = 4), trauma (N = 1), neoplasm (N = 1) and unknown (N = 15). Rhinologic disease included chronic rhinosinusitis (N = 3) and other nasal anatomic lesions. None of the four subjects with congenital anosmia had classic Kallmann syndrome. The utility of imaging in confirming an etiology of anosmia was noted in 1 of 8 CT and 5 of 22 MRI. The most significant finding of the questionnaire was confirmation of normal puberty in the congenital group.

Conclusion: Similar to the adult population, rhinologic disease is the most common cause. Absence or hypoplasia of the olfactory bulbs without associated delayed puberty is the presentation of congenital anosmia in our cohort. MRI had a higher utility than CT in evaluating anosmia in general and congenital anosmia in specific. MRI to evaluate children with a history of congenital olfactory dysfunction is recommended.
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http://dx.doi.org/10.1016/j.ijporl.2018.05.011DOI Listing
July 2018

Imaging of congenital central nervous system infections.

Pediatr Radiol 2018 04 17;48(4):513-523. Epub 2018 Mar 17.

Department of Radiology, Children's Hospital Colorado, University of Colorado School of Medicine, 13123 E. 16th Ave., Box B125, Aurora, CO, 80045, USA.

Congenital central nervous system (CNS) infections are a cause of significant morbidity and mortality. The recent Zika virus outbreak raised awareness of congenital CNS infections. Imaging can be effective in diagnosing the presence and severity of infection. In this paper we review the clinical presentations and imaging characteristics of several common and less common congenital CNS infections.
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http://dx.doi.org/10.1007/s00247-018-4092-1DOI Listing
April 2018

Frontal and occipital horn ratio is associated with multifocal intraparenchymal hemorrhages in neonatal shunted hydrocephalus.

J Neurosurg Pediatr 2017 Nov 8;20(5):432-438. Epub 2017 Sep 8.

Radiology, and.

OBJECTIVE Placement of a cerebrospinal fluid diversion device (i.e., shunt) is a routine pediatric neurosurgical procedure, often performed in the first weeks of life for treatment of congenital hydrocephalus. In the postoperative period, shunt placement may be complicated by subdural, catheter tract, parenchymal, and intraventricular hemorrhages. The authors observed a subset of infants and neonates who developed multifocal intraparenchymal hemorrhages (MIPH) following shunt placement and sought to determine any predisposing perioperative variables. METHODS A retrospective review of the electronic medical record at a tertiary-care children's hospital was performed for the period 1998-2015. Inclusion criteria consisted of shunt placement, age < 30 days, and available pre- and postoperative brain imaging. The following data were collected and analyzed for each case: ventricular size ratios, laboratory values, clinical presentation, shunt and valve type, and operative timing and approach. RESULTS A total of 121 neonates met the inclusion criteria for the study, and 11 patients (9.1%) had MIPH following shunt placement. The preoperative frontal and occipital horn ratio (FOR) was significantly higher in the patients with MIPH than in those without (0.65 vs 0.57, p < 0.001). The change in FOR (∆FOR) after shunt placement was significantly greater in the MIPH group (0.14 vs 0.08, p = 0.04). Among neonates who developed MIPH, aqueductal stenosis was the most common etiology (45%). The type of shunt valve was associated with incidence of MIPH (p < 0.001). Preoperative clinical parameters, including head circumference, bulging fontanelle, and coagulopathy, were not significantly associated with development of MIPH. CONCLUSIONS MIPH represents an underrecognized complication of neonatal shunted hydrocephalus. Markers of severity of ventriculomegaly (FOR) and ventricular response to CSF diversion (∆FOR) were significantly associated with occurrence of MIPH. Choice of shunt and etiology of hydrocephalus were also significantly associated with MIPH. After adjusting for corrected age, etiology of hydrocephalus, and shunt setting, the authors found that ∆FOR after shunting was still associated with MIPH. A prospective study of MIPH prevention strategies and assessment of possible implications for patient outcomes is needed.
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http://dx.doi.org/10.3171/2017.6.PEDS16481DOI Listing
November 2017

Predicting Progression of Intracranial Arteriopathies in Childhood Stroke With Vessel Wall Imaging.

Stroke 2017 08 5;48(8):2274-2277. Epub 2017 Jul 5.

From the Department of Radiology (N.V.S., D.M.M.) and Departments of Pediatrics and Pediatric Neurology (T.J.B.), Children's Hospital Colorado, Aurora; and Hemophilia and Thrombosis Center (L.L.P., A.L.H., T.J.B.), Department of Anesthesiology (P.S.H., R.J.T.), and Department Neurology (S.P.), University of Colorado Denver, Aurora.

Background And Purpose: Childhood arterial ischemic stroke is frequently associated with an intracranial arteriopathy that often progresses in the first 3 to 6 months post stroke. We hypothesized that children with enhancing arteriopathies on vessel wall imaging (VWI) would have a higher risk of arteriopathy progression than those without enhancement.

Methods: Our institutional radiographic database was searched for cases of childhood stroke with VWI. Inclusion criteria consisted of age ranging from 1 month through 20 years, diagnosis of arterial ischemic stroke, available VWI, and follow-up magnetic resonance angiogram. Imaging was reviewed to systematically describe VWI findings, categorize arteriopathies, steroid therapy, and identify progressive arteriopathies using CACADE definitions.

Results: Sixteen cases of childhood stroke at Children's Hospital Colorado between January 1, 2010 and July 1, 2016 were reviewed. Strong vessel wall enhancement at presentation was associated with progressive arteriopathy in 83% of cases (10/12), when compared with 0% (0/4) without strong enhancement (=0.008).

Conclusions: Our case series demonstrates the potential benefit of VWI in children with stroke because it may identify patients who will have progressive arterial disease.
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http://dx.doi.org/10.1161/STROKEAHA.117.017922DOI Listing
August 2017