Fetal head and neck tumors.

Imaging plays a leading role in detection and diagnosis of fetal head and neck lesions. These lesions comprise a heterogeneous group of congenital tumors and malformations. Complementary imaging modalities that can be used in prenatal medicine are ultrasound and MRI. The authors discuss imaging characteristics of fetal lesions, assessment of potential complications and pregnancy management options for the most common pathology of the fetal head and neck.

Neurologic challenges in 22q11.2 deletion syndrome.

Children with 22q11.2 deletion syndrome often come to medical attention due to signs and symptoms of neurologic dysfunction. It is imperative to understand the expected neurologic development of patients with this diagnosis in order to be alert for the potential neurologic complications, including cortical malformations, tethered cord, epilepsy, and movement disorders. We present an update of brain imaging findings from the CHOP 22q and You Center, a review of the current literature, and our current management practices for neurological issues.

N-acetylaspartate supports the energetic demands of developmental myelination via oligodendroglial aspartoacylase.

Breakdown of neuro-glial N-acetyl-aspartate (NAA) metabolism results in the failure of developmental myelination, manifest in the congenital pediatric leukodystrophy Canavan disease caused by mutations to the sole NAA catabolizing enzyme aspartoacylase. Canavan disease is a major point of focus for efforts to define NAA function, with available evidence suggesting NAA serves as an acetyl donor for fatty acid synthesis during myelination. Elevated NAA is a diagnostic hallmark of Canavan disease, which contrasts with a broad spectrum of alternative neurodegenerative contexts in which levels of NAA are inversely proportional to pathological progression. Recently generated data in the nur7 mouse model of Canavan disease suggests loss of aspartoacylase function results in compromised energetic integrity prior to oligodendrocyte death, abnormalities in myelin content, spongiform degeneration, and motor deficit. The present study utilized a next-generation "oligotropic" adeno-associated virus vector (AAV-Olig001) to quantitatively assess the impact of aspartoacylase reconstitution on developmental myelination. AAV-Olig001-aspartoacylase promoted normalization of NAA, increased bioavailable acetyl-CoA, and restored energetic balance within a window of postnatal development preceding gross histopathology and deteriorating motor function. Long-term effects included increased oligodendrocyte numbers, a global increase in myelination, reversal of vacuolation, and rescue of motor function. Effects on brain energy observed following AAV-Olig001-aspartoacylase gene therapy are shown to be consistent with a metabolic profile observed in mild cases of Canavan disease, implicating NAA in the maintenance of energetic integrity during myelination via oligodendroglial aspartoacylase.

Childhood encephalitis: relationship between diffusion abnormalities and clinical outcome.

INTRODUCTION: The impact of restricted diffusion on clinical outcome has not been well studied in childhood encephalitis. We hypothesized that the patients with lesions with restricted diffusion (LRD) would have worse clinical outcome. METHODS: We reviewed the MR studies of 83 children with encephalitis for LRD. An MRI scoring system (0-12) based on fluid-attenuated inversion recovery (FLAIR) imaging was created to evaluate the extent of imaging abnormality. Clinical outcome was graded by using Glasgow outcome scale (GOS) (1-5) in 1st and 12th month: 1 for death and five for full recovery. With respect to diffusion, the correlation between imaging score and GOS was assessed. Logistic regression analysis was used to explore the impact of diffusion and imaging score on clinical outcome. The patients were divided into three subgroups regarding imaging score: I, 0-4; II, 5-8; and III, 9-12. RESULTS: LRD was found in 28 patients. Negative significant correlation was found between imaging score and GOS in the group with LRD in both 1st month (R = -0.67, P < 0.001) and 12th month (R = -0.56, P = 0.001). Multivariate logistic regression showed that LRD (P < 0.001) and age (P = 0.026) were significant independent risk factors for unfavorable outcome in 1st month, and both LRD (P = 0.001) and imaging score (P = 0.043) were significant risk factors for unfavorable outcome in 12th month. CONCLUSIONS: Patients with LRD have a worse clinical outcome than those without LRD. In patients with LRD, those with a greater extent of abnormality have a poorer outcome.

Morphology of the foramen magnum in syndromic and non-syndromic brachycephaly.

PURPOSE: The shape and size of the foramen magnum (FM) can be altered in craniosynostoses. However, few studies have investigated these changes. In this paper, we investigate the morphology of the foramen magnum in syndromic and non-syndromic brachycephaly. METHODS: Surface area, anteroposterior (AP) diameter, and transverse diameters of the FM were measured on high-resolution CT scans in children with Crouzon (25), Pfeiffer (21), Apert (26), Saethre-Chotzen (7) syndromes, and isolated bicoronal synostosis (9) and compared to an age-matched control group (30). RESULTS: A significantly smaller FM surface area was observed in Crouzon (6.3 ± 1.7 cm(2)) and Pfeiffer (6.4 ± 2.3 cm(2)) syndromes as compared to the control group (7.4 ± 1.3 cm(2), p = 0.006 and p = .017, respectively). In comparison to the control group, no statistically significant alteration in FM surface area was noted in patients with Apert, Saethre-Chotzen, or isolated bicoronal synostosis (p = 0.37, p = 0.71, p = 0.40 respectively). The transverse diameter of FM was significantly smaller in Crouzon, Pfeiffer, and Apert syndromes compared to the control group (p = 0.005, p = 0.002, p = 0.03 respectively). In Saethre-Chotzen and isolated bicoronal synostosis, no difference in transverse diameter was demonstrated. Among all groups, only Crouzon syndrome showed reduced anteroposterior diameter as compared to controls (p = 0.005). In Pfeiffer and Apert syndromes, there was elongation of the shape of the FM with a relatively narrowed width as demonstrated in a significantly increased AP to transverse diameter ratio (p = 0.002 and p = 0.019, respectively). DISCUSSION AND CONCLUSIONS: The FM shape and area is significantly altered in fibroblast growth factor receptor (FGFR)-related brachycephaly syndromes (Crouzon, Pfeiffer, and Apert), whereas in patients with Saethre-Chotzen syndrome (TWIST-1 mutation) and isolated non-syndromic bicoronal synostosis, the shape and mean FM area was not statistically different from that of normals. This study brings to light the important role of FGFRs on FM growth and shape. TWIST-1 mutation (Saethre-Chotzen syndrome) does not appear to have an important effect in shaping the FM.

Hemizygous mutations in SNAP29 unmask autosomal recessive conditions and contribute to atypical findings in patients with 22q11.2DS.

BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder, affecting an estimated 1 : 2000-4000 live births. Patients with 22q11.2DS have a broad spectrum of phenotypic abnormalities which generally includes congenital cardiac abnormalities, palatal anomalies, and immunodeficiency. Additional findings, such as skeletal anomalies and autoimmune disorders, can confer significant morbidity in a subset of patients. 22q11.2DS is a contiguous gene DS and over 40 genes are deleted in patients; thus deletion of several genes within this region contributes to the clinical features. Mutations outside or on the remaining 22q11.2 allele are also known to modify the phenotype. METHODS: We utilised whole exome, targeted exome and/or Sanger sequencing to examine the genome of 17 patients with 22q11.2 deletions and phenotypic features found in <10% of affected individuals. RESULTS AND CONCLUSIONS: In four unrelated patients, we identified three novel mutations in SNAP29, the gene implicated in the autosomal recessive condition cerebral dysgenesis, neuropathy, ichthyosis and keratoderma (CEDNIK). SNAP29 maps to 22q11.2 and encodes a soluble SNARE protein that is predicted to mediate vesicle fusion at the endoplasmic reticulum or Golgi membranes. This work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to mutations on the non-deleted chromosome, which leads to unmasking of autosomal recessive conditions such as CEDNIK, Kousseff, and a potentially autosomal recessive form of Opitz G/BBB syndrome. Furthermore, our work implicates SNAP29 as a major modifier of variable expressivity in 22q11.2 DS patients.

Prenatal Repair of Myelomeningocele and School-age Functional Outcomes.

BACKGROUND AND OBJECTIVES: The Management of Myelomeningocele Study (MOMS), a randomized trial of prenatal versus postnatal repair for myelomeningocele, found that prenatal surgery resulted in reduced hindbrain herniation and need for shunt diversion at 12 months of age and better motor function at 30 months. In this study, we compared adaptive behavior and other outcomes at school age (5.9-10.3 years) between prenatal versus postnatal surgery groups. METHODS: Follow-up cohort study of 161 children enrolled in MOMS. Assessments included neuropsychological and physical evaluations. Children were evaluated at a MOMS center or at a home visit by trained blinded examiners. RESULTS: The Vineland composite score was not different between surgery groups (89.0 ± 9.6 in the prenatal group versus 87.5 ± 12.0 in the postnatal group; P = .35). Children in the prenatal group walked without orthotics or assistive devices more often (29% vs 11%; P = .06), had higher mean percentage scores on the Functional Rehabilitation Evaluation of Sensori-Neurologic Outcomes (92 ± 9 vs 85 ± 18; P < .001), lower rates of hindbrain herniation (60% vs 87%; P < .001), had fewer shunts placed for hydrocephalus (49% vs 85%; P < .001) and, among those with shunts, fewer shunt revisions (47% vs 70%; P = .02) than those in the postnatal group. Parents of children repaired prenatally reported higher mean quality of life z scores (0.15 ± 0.67 vs 0.11 ± 0.73; P = .008) and lower mean family impact scores (32.5 ± 7.8 vs 37.0 ± 8.9; P = .002). CONCLUSIONS: There was no significant difference between surgery groups in overall adaptive behavior. Long-term benefits of prenatal surgery included improved mobility and independent functioning and fewer surgeries for shunt placement and revision, with no strong evidence of improved cognitive functioning.

Imaging of Pediatric Hearing Loss.

Temporal bone high-resolution computed tomography (HRCT) and magnetic resonance (MR) imaging are valuable tools in the evaluation of pediatric hearing loss. Computed tomography is important in the evaluation of pediatric conductive hearing loss and is the imaging modality of choice for evaluation of osseous abnormalities. MR imaging is the modality of choice for evaluation of sensorineural hearing loss. A broad spectrum of imaging findings can be seen with hearing loss in children. HRCT and MR imaging provide complementary information and are often used in conjunction in the preoperative evaluation of pediatric candidates for cochlear implantation.

A prospective, randomized, multicenter trial of amnioreduction vs selective fetoscopic laser photocoagulation for the treatment of severe twin-twin transfusion syndrome.

OBJECTIVE: The objective of the study was to examine the effect of selective fetoscopic laser photocoagulation (SFLP) vs serial amnioreduction (AR) on perinatal mortality in severe twin-twin transfusion syndrome (TTTS). STUDY DESIGN: This was a 5 year multicenter, prospective, randomized controlled trial. The primary outcome variable was 30 day postnatal survival of donors and recipients. RESULTS: There was no statistically significant difference in 30-day postnatal survival between SFLP or AR treatment for donors at 55% (11 of 20) vs 55% (11 of 20) (P = 1.0, odds ratio [OR] 1, 95% confidence interval [CI] 0.242 to 4.14) or recipients at 30% (6 of 20) vs 45% (9 of 20) (P = .51, OR 1.88, 95% CI 0.44 to 8.64). There was no difference in 30 day survival of 1 or both twins on a per-pregnancy basis between AR at 75% (15 of 20) and SFLP at 65% (13 of 20) (P = .73, OR 1.62, 95% CI 0.34 to 8.09). Overall survival (newborns divided by the number of fetuses treated) was not statistically significant for AR at 60% (24 of 40) vs SFLP 45% (18 of 40) (P = .18, OR 2.01, 95% CI 0.76 to 5.44). There was a statistically significant increase in fetal recipient mortality in the SFLP arm at 70% (14 of 20) vs the AR arm at 35% (7 of 20) (P = .25, OR 5.31, 95% CI 1.19 to 27.6). This was offset by increased recipient neonatal mortality of 30% (6 of 20) in the AR arm. Echocardiographic abnormality in recipient twin Cardiovascular Profile Score is the most significant predictor of recipient mortality (P = .055, OR 3.025/point) by logistic regression analysis. CONCLUSION: The outcome of the trial did not conclusively determine whether AR or SFLP is a superior treatment modality. TTTS cardiomyopathy appears to be an important factor in recipient survival in TTTS.

CT-guided percutaneous steroid injection for management of inflammatory arthropathy of the temporomandibular joint in children.

OBJECTIVE: The purposes of this study were to retrospectively review an injection technique, to develop a grading system for evaluation of imaging findings, and to report preliminary outcome related to percutaneous CT-guided steroid injection into the temporomandibular joints of children with inflammatory arthropathy. CONCLUSION: CT-guided steroid injection into the temporomandibular joint of children with inflammatory arthropathy results in clinical and imaging improvement in a substantial proportion of children treated.

3.0 T versus 1.5 T pediatric brain imaging.

This article represents a review of the authors' experience with two 3.0 T Siemens Trio Whole Body MR imaging units, with a cumulative experience of 12 months total imaging time on these scanners, over 1000 cases. The authors were able to identify and review numerous patients who had diagnostic studies both on 1.5 T and 3.0 T.

Neuroimaging evaluation of cerebral palsy.

MRI can demonstrate and differentiate the various insults and anomalies that can be responsible for cerebral palsy. Recent advances have resulted in techniques and sequences that allow prompt detection of cytotoxic edema and evaluation of brain perfusion. MRI precisely demonstrates the various patterns of injury, distinguishing insults owing to profound asphyxia, partial prolonged asphyxia, and mixed partial prolonged and profound asphyxia. Infants and children can be studied with MRI, and ultrafast MRI permits evaluation of the fetal central nervous system. In the fetus, the cause of ventriculomegaly can be determined, such as cerebrospinal fluid flow obstruction, brain malformation, or brain destruction with or without hemorrhage. Results from fetal MRI have led to better understanding of many brain abnormalities.

Risk of optic pathway glioma in children with neurofibromatosis type 1 and optic nerve tortuosity or nerve sheath thickening.

BACKGROUND/AIMS: Optic nerve tortuosity and nerve and sheath thickening are observed on MRI in some patients with neurofibromatosis type 1 (NF-1). This study aimed to determine if tortuosity and thickening are associated with the development of optic pathway glioma (OPG) and subsequent vision loss. METHODS: Children with NF-1 who underwent brain MRI between 1992 and 2005, and had at least 1 year of subsequent visual acuity (VA) follow-up, were identified retrospectively. The baseline MRI was independently reviewed by three neuroradiologists for consensus assessment. Tortuosity was identified using validated operational criteria. Optic nerve and sheath thicknesses and VA at last follow-up were directly measured. RESULTS: Of 132 evaluable children, seven (5%) had tortuosity on baseline MRI. 20 subjects (15%) ultimately developed OPG at a median of 1.9 years (range 7 months-8.0 years) following the baseline MRI. Subjects with tortuosity were significantly more likely to develop OPG than those without tortuosity (57% vs 13%, p=0.01). In subjects who developed OPG, the prevalence of tumour-related vision loss was not significantly different between those with and without baseline tortuosity (14% vs 4%, p=0.28). No difference existed between mean baseline optic nerve (2.3 vs 2.2 mm) or sheath (5.2 vs 5.4 mm) thicknesses comparing subjects who did and did not develop OPG. CONCLUSIONS: Optic nerve tortuosity at baseline is associated with OPG development among patients with NF-1, but does not predispose to aggressive OPG with associated vision loss. Neither nerve nor sheath thickening at baseline is associated with OPG development.

Diffusion-weighted MR imaging of early methotrexate-related neurotoxicity in children.

BACKGROUND AND PURPOSE: Methotrexate is a major cause of treatment-related acute neurotoxicity in children with hematologic malignancies. The purpose of this study was to investigate whether diffusion-weighted MR imaging (DWI) detects acute methotrexate white matter neurotoxicity in this patient population. METHODS: Six children-three female and three male-with hematologic malignancies were studied at time of onset of neurologic dysfunction during the delayed intensification or consolidation phase of therapy, when intensive intrathecal methotrexate is given. MR imaging including DWI was performed on 1.5 T MR scanners. RESULTS: DWI demonstrated abnormal restriction of motion of water in the centrum semiovale in all six patients. This finding correlated to the acute onset of hemiparesis or aphasia. Fluid-attenuated inversion recovery imaging was not positive at this time, but it was positive in all five patients in whom follow-up imaging was performed. CONCLUSION: Early detection of methotrexate white matter injury by DWI has the potential to alert the oncologist to this event and provide a technique by which treatment of neurotoxicity can be monitored.

Magnetic resonance evaluation of fetal ventriculomegaly-associated congenital malformations and lesions.

Fetal MRI provides diagnostic quality images of the brain which permit differentiation between the various etiologies of ventriculomegaly: hydrocephalus, congenital malformation, and destructive processes.

Lithium citrate for Canavan disease.

Current evidence suggests that the effects of lithium on metabolic and signaling pathways in the brain may vary depending on the specific clinical condition or disease model. For example, lithium increases levels of cerebral N-acetyl aspartate in patients with bipolar disorder but does not appear to affect N-acetyl aspartate levels in normal human subjects. Conversely, lithium significantly decreases whole-brain levels of N-acetyl aspartate in a rat genetic model of Canavan disease in which cerebral N-acetyl aspartate is chronically elevated. While N-acetyl aspartate is a commonly used surrogate marker for neuronal density and correlates with neuronal viability, grossly elevated whole-brain levels of N-acetyl aspartate in Canavan disease are associated with dysmyelination and mental retardation. This report describes the first clinical application of lithium in a human subject with Canavan disease. Spectroscopic and clinical changes were observed over the time period in which lithium was administered, which reversed during a 2-week wash-out period after withdrawal of lithium. This investigation reports decreased N-acetyl aspartate levels in the brain regions tested and magnetic resonance spectroscopic values that are more characteristic of normal development and myelination, suggesting that a larger, controlled trial of lithium may be warranted as supportive therapy for Canavan disease by decreasing abnormally elevated N-acetyl aspartate.

Vascular lesions of the orbit in children.

Hemangioma and venous lymphatic malformation are the two most common orbital vascular lesions occurring in the pediatric patient. MR imaging precisely delineates and characterizes these lesions and thus plays an important role in their diagnosis and management. This article discusses the characteristic clinical and imaging findings of hemangiomas and venous lymphatic malformations and the controversies regarding the origin and nomenclature of vascular lesions.

Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain.

This clinical protocol describes virus-based gene transfer for Canavan disease, a childhood leukodystrophy. Canavan disease, also known as Van Bogaert-Bertrand disease, is a monogeneic, autosomal recessive disease in which the gene coding for the enzyme aspartoacylase (ASPA) is defective. The lack of functional enzyme leads to an increase in the central nervous system of the substrate molecule, N-acetyl-aspartate (NAA), which impairs normal myelination and results in spongiform degeneration of the brain. No effective treatment currently exists; however, virus-based gene transfer has the potential to arrest or reverse the course of this otherwise fatal condition. This procedure involves neurosurgical administration of approximately 900 billion genomic particles (approximately 10 billion infectious particles) of recombinant adeno-associated virus (AAV) containing the aspartoacylase gene (ASPA) directly to affected regions of the brain in each of 21 patients with Canavan disease. Pre- and post-delivery assessments include a battery of noninvasive biochemical, radiological, and neurological tests. This gene transfer study represents the first clinical use of AAV in the human brain and the first instance of viral gene transfer for a neurodegenerative disease.