Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome.

Xq22 deletions that encompass PLP1 (Xq22-PLP1-DEL) are notable for variable expressivity of neurological disease traits in females ranging from a mild late-onset form of spastic paraplegia type 2 (MIM# 312920), sometimes associated with skewed X-inactivation, to an early-onset neurological disease trait (EONDT) of severe developmental delay, intellectual disability, and behavioral abnormalities. Size and gene content of Xq22-PLP1-DEL vary and were proposed as potential molecular etiologies underlying variable expressivity in carrier females where two smallest regions of overlap (SROs) were suggested to influence disease. We ascertained a cohort of eight unrelated patients harboring Xq22-PLP1-DEL and performed high-density array comparative genomic hybridization and breakpoint-junction sequencing. Molecular characterization of Xq22-PLP1-DEL from 17 cases (eight herein and nine published) revealed an overrepresentation of breakpoints that reside within repeats (11/17, ~65%) and the clustering of ~47% of proximal breakpoints in a genomic instability hotspot with characteristic non-B DNA density. These findings implicate a potential role for genomic architecture in stimulating the formation of Xq22-PLP1-DEL. The correlation of Xq22-PLP1-DEL gene content with neurological disease trait in female cases enabled refinement of the associated SROs to a single genomic interval containing six genes. Our data support the hypothesis that genes contiguous to PLP1 contribute to EONDT.

Expansion of the clinical spectrum associated with AARS2-related disorders.

Biallelic pathogenic variants in AARS2, a gene encoding the mitochondrial alanyl-tRNA synthetase, result in a spectrum of findings ranging from infantile cardiomyopathy to adult-onset progressive leukoencephalopathy. In this article, we present three unrelated individuals with novel compound heterozygous pathogenic AARS2 variants underlying diverse clinical presentations. Patient 1 is a 51-year-old man with adult-onset progressive cognitive, psychiatric, and motor decline and leukodystrophy. Patient 2 is a 34-year-old man with childhood-onset progressive tremor followed by the development of polyneuropathy, ataxia, and mild cognitive and psychiatric decline without leukodystrophy on imaging. Patient 3 is a 57-year-old woman with childhood-onset tremor and nystagmus which preceded dystonia, chorea, ataxia, depression, and cognitive decline marked by cerebellar atrophy and white matter disease. These cases expand the clinical heterogeneity of AARS2-related disorders, given that the first and third case represent some of the oldest known survivors of this disease, the second is adult-onset AARS2-related neurological decline without leukodystrophy, and the third is biallelic AARS2-related disorder involving a partial gene deletion.

The spectrum of brainstem malformations associated to mutations of the tubulin genes family: MRI and DTI analysis.

OBJECTIVES: To describe the spectrum of brainstem malformations associated to mutations in the tubulin genes taking advantage of magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). METHODS: Fifteen patients (six males; median age, 1.25 years; range, 1 month to 31 years) with mutations in the tubulin genes (TUBA1A = 8, TUBB2B = 4, TUBB3 = 3) studied with MRI and DTI were included in the study. Brain MR exams were reviewed to describe the malformative aspects of the brainstem. Malformations of the supratentorial brain and cerebellum were also recorded. Tractography was performed in seven selected cases. RESULTS: Fourteen patients (93%) showed complex malformations of the brainstem. Most common findings, apparent on anatomical MR sequences, were brainstem asymmetry (12 cases, 5 of which with a crossed pattern characterised by a hypertrophic right medulla oblongata and hypertrophic left pons), short and small pons on midline (10 cases) and anterior brainstem clefting (6 cases). DTI revealed abnormal transverse pontine fibres (13 cases), fusion of corticospinal tracts and medial lemnisci (9 cases) and a small decussation of the superior cerebellar peduncles (7 cases). CONCLUSIONS: Conventional/anatomical MRI and DTI reveal a complex pattern of brainstem malformations associated with tubulin genes mutations. KEY POINTS: • Brainstem malformations affect 93% patients with mutated tubulin genes • MRI shows homolateral and crossed brainstem asymmetries, clefts and pons hypoplasia • DTI demonstrates irregular representation of transverse pontine fibres and fusion of corticospinal tracts.

Arrested Hydrocephalus in Childhood: Case Series and Review of the Literature.

INTRODUCTION: Hydrocephalus can be progressive or spontaneously arrested. In arrested hydrocephalus, the balance between production and absorption of the cerebrospinal fluid is restored. Patients are mostly asymptomatic, and no surgical treatment is necessary for them. METHODS: We performed a two-center consecutive case series study, aimed at investigating the safety of nonsurgical management of hydrocephalus in selected pediatric patients. We retrospectively selected all consecutive patients, suspected to suffer from arrested hydrocephalus and referred to our two institutions between January 2011 and December 2013. Data on clinical and radiological follow-up were collected until June 2017. RESULTS: Five children diagnosed with arrested hydrocephalus were included in the study. All patients presented macrocephaly as the main presenting sign. Associated mild-to-moderate stable motor disorders were assessed in four out of five cases. Typical symptoms and signs associated with acute raised intracranial pressure were absent in all patients. Magnetic resonance imaging studies showed ventriculomegaly in all patients. A diagnosis of arrested hydrocephalus was made in all five cases based on stable clinical and radiological findings during the initial observation. Conservative management based on active surveillance was, therefore, proposed. During the follow-up period, we observed stable or improved conditions in four out of five patients, while the remaining patient presented progressive hydrocephalus. DISCUSSION: Making a distinction between arrested and progressive hydrocephalus is fundamental, because of the opposed appropriate management. Any newly discovered case of hydrocephalus, not characterized by clear signs of progressive hydrocephalus, should benefit from active surveillance before any definitive decision is taken.

Joubert syndrome: neuroimaging findings in 110 patients in correlation with cognitive function and genetic cause.

BACKGROUND: Joubert syndrome is a clinically and genetically heterogeneous ciliopathy. Neuroimaging findings have not been systematically evaluated in a large cohort of patients with Joubert syndrome in correlation with molecular genetic cause and cognitive function. METHODS: Brain MRI of 110 patients with Joubert syndrome was included in this study. A comprehensive evaluation of brain MRI studies for infratentorial and supratentorial morphological abnormalities was performed. Genetic cause was identified by whole-exome sequencing, and cognitive functions were assessed with age-appropriate neurocognitive tests in a subset of patients. RESULTS: The cerebellar hemispheres were enlarged in 18% of the patients, mimicking macrocerebellum. The posterior fossa was enlarged in 42% of the patients, resembling Dandy-Walker malformation. Abnormalities of the brainstem, such as protuberance at the ventral contour of the midbrain, were present in 66% of the patients. Abnormalities of the supratentorial brain were present in approximately one-third of the patients, most commonly malrotation of the hippocampi. Mild ventriculomegaly, which typically did not require shunting, was present in 23% of the patients. No correlation between neuroimaging findings and molecular genetic cause was apparent. A novel predictor of outcome was identified; the more severe the degree of vermis hypoplasia, the worse the neurodevelopmental outcome was. CONCLUSIONS: The spectrum of neuroimaging findings in Joubert syndrome is wide. Neuroimaging does not predict the genetic cause, but may predict the neurodevelopmental outcome. A high degree of vermis hypoplasia correlates with worse neurodevelopmental outcome. This finding is important for prognostic counselling in Joubert syndrome.

Diffusion Tensor Imaging Detects Occult Cerebellar Injury in Severe Neonatal Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Despite the benefits of whole-body hypothermia therapy, many infants with hypoxic-ischemic encephalopathy (HIE) die or have significant long-term neurodevelopmental impairment. Prospectively identifying neonates at risk of poor outcome is essential but not straightforward. The cerebellum is not classically considered to be a brain region vulnerable to hypoxic-ischemic insults; recent literature suggests, however, that the cerebellum may be involved in neonatal HIE. In this study, we aimed to assess the microstructural integrity of cerebellar and linked supratentorial structures in neonates with HIE compared to neurologically healthy neonatal controls. METHODS: In this prospective cohort study, we performed a quantitative diffusion tensor imaging (DTI) analysis of the structural pathways of connectivity, which may be affected in neonatal cerebellar injury by measuring fractional anisotropy (FA) and mean diffusivity (MD) within the superior, middle, and inferior cerebellar peduncles, dentate nuclei, and thalami. All magnetic resonance imaging (MRI) studies were grouped into 4 categories of severity based on a qualitative evaluation of conventional and advanced MRI sequences. Multivariable linear regression analysis of cerebellar scalars of patients and controls was performed, controlling for gestational age, age at the time of MRI, and HIE severity. Spearman rank correlation was performed to correlate DTI scalars of the cerebellum and thalami. RESULTS: Fifty-seven (23 females, 40%) neonates with HIE and 12 (6 females, 50%) neonatal controls were included. There were 8 patients (14%) in HIE severity groups 3 and 4 (injury of the basal ganglia/thalamus and/or cortex). Based on a qualitative analysis of conventional and DTI images, no patients had evidence of cerebellar injury. No significant differences between patients and controls were found in the FA and MD scalars. However, FA values of the middle cerebellar peduncles (0.294 vs. 0.380, p < 0.001) and MD values of the superior cerebellar peduncles (0.920 vs. 1.007 × 10-3 mm/s2, p = 0.001) were significantly lower in patients with evidence of moderate or severe injury on MRI (categories 3 and 4) than in controls. In patients, cerebellar DTI scalars correlated positively with DTI scalars within the thalami. CONCLUSION: Our results suggest that infants with moderate-to-severe HIE may have occult injury of cerebellar white-matter tracts, which is not detectable by the qualitative analysis of neuroimaging data alone. Cerebellar DTI scalars correlate with thalamic measures, highlighting that cerebellar injury is unlikely to occur in isolation and may reflect the severity of HIE. The impact of concomitant cerebellar injury in HIE on long-term neurodevelopmental outcome warrants further study.

Optimizing Cerebral Autoregulation May Decrease Neonatal Regional Hypoxic-Ischemic Brain Injury.

BACKGROUND: Therapeutic hypothermia provides incomplete neuroprotection for neonatal hypoxic-ischemic encephalopathy (HIE). We examined whether hemodynamic goals that support autoregulation are associated with decreased brain injury and whether these relationships are affected by birth asphyxia or vary by anatomic region. METHODS: Neonates cooled for HIE received near-infrared spectroscopy autoregulation monitoring to identify the mean arterial blood pressure with optimized autoregulatory function (MAPOPT). Blood pressure deviation from MAPOPT was correlated with brain injury on MRI after adjusting for the effects of arterial carbon dioxide, vasopressors, seizures, and birth asphyxia severity. RESULTS: Blood pressure deviation from MAPOPT related to neurologic injury in several regions independent of birth asphyxia severity. Greater duration and deviation of blood pressure below MAPOPT were associated with greater injury in the paracentral gyri and white matter. Blood pressure within MAPOPT related to lesser injury in the white matter, putamen and globus pallidus, and brain stem. Finally, blood pressures that exceeded MAPOPT were associated with reduced injury in the paracentral gyri. CONCLUSIONS: Blood pressure deviation from optimal autoregulatory vasoreactivity was associated with MRI markers of brain injury that, in many regions, were independent of the initial birth asphyxia. Targeting hemodynamic ranges to optimize autoregulation has potential as an adjunctive therapy to hypothermia for HIE.

Cerebellar Microstructural Organization is Altered by Complications of Premature Birth: A Case-Control Study.

OBJECTIVES: To compare regional cerebellar microstructure, as measured by diffusion tensor imaging (DTI), between preterm infants at term-equivalent age and healthy term-born control neonates, and to explore associations between DTI findings and clinical risk factors. STUDY DESIGN: In this case-control study, DTI studies were performed in 73 premature infants born ≤32 weeks and ≤1500 g birth weight and 73 full-term-born controls from healthy pregnancies. Using a region of interest approach, fractional anisotropy (FA) and mean diffusivity (MD) were extracted in 7 cerebellar regions including the anterior vermis, the right/left superior cerebellar peduncles, the middle cerebellar peduncle, and the dentate nuclei. To validate further our DTI measurements, we measured FA and MD in the genu of the corpus callosum and splenium. FA and MD were compared between groups using analyses of multiple linear regression models. RESULTS: Preterm infants at term-equivalent age presented with higher FA in the dentate nuclei (<.001) and middle cerebellar peduncle (.028), and lower MD in the vermis (.023) compared with controls. Conversely, preterm infants showed reduced FA and increased MD in both the genu of the corpus callosum and splenium (P < .001). Independent risk factors associated with altered FA and MD in the cerebellum included low Apgar score, supratentorial injury, compromised cardiorespiratory function, and surgery for necrotizing enterocolitis and patent ductus arteriosus. CONCLUSIONS: This DTI study provides evidence that complications of premature birth are associated with altered cerebellar microstructural organization when compared with term-born control infants.

Neuropsychological phenotypes of 76 individuals with Joubert syndrome evaluated at a single center.

Joubert syndrome (JS) is a genetically heterogeneous ciliopathy characterized by hypo-dysplasia of the cerebellar vermis, a distinct hindbrain/midbrain malformation (molar tooth sign), and intellectual disability. We evaluated the neuropsychological profiles of 76 participants with JS in the context of molecular genetics and clinical covariates. Evaluations included neuropsychological testing, structured parental interviews, DNA sequencing, brain magnetic resonance imaging (MRI), electroencephalography (EEG), ophthalmologic examination, and assessment for renal and hepatic disease. On average, participants manifested Full Scale Intelligence Quotients (FSIQ) in the moderately to profoundly low range (M = 64.3 ± 15.3). Of the Wechsler index scores, verbal comprehension was least affected and processing speed was most affected. Receptive language was rated as better than expressive language on the Vineland Adaptive Behavior Scales-Second Edition. Those with abnormal EEG had a significantly lower FSIQ (n = 15; M = 50.7 ± 12.9) compared to participants with normal EEG (n = 39; M = 64.7 ± 16.3; p = .004). Participants taking psychiatric medications manifested a lower FSIQ (n = 20; M = 54.8 ± 13.2) than those not taking them (n = 42; M = 65.0 ± 17.2; p = .022). These correlations were also present in the TMEM67-related JS sub-cohort (n = 14). Based on parental assessment, psychiatric and behavioral problems were significantly more common than in the general population for all measures (p < .004 for all). The majority (65%) of individuals with JS have some degree of intellectual disability. Abnormal EEG is associated with lower neuropsychological function. Processing speed is a weakness, while verbal comprehension and receptive language are relative strengths. These findings may guide parents, teachers, therapists, and doctors to determine appropriate therapies, accommodations, and academic goals for individuals with JS.

Tubulin-related cerebellar dysplasia: definition of a distinct pattern of cerebellar malformation.

OBJECTIVE: To determine the neuroimaging pattern of cerebellar dysplasia (CD) and other posterior fossa morphological anomalies associated with mutations in tubulin genes and to perform clinical and genetic correlations. METHODS: Twenty-eight patients harbouring 23 heterozygous pathogenic variants (ten novel) in tubulin genes TUBA1A (n = 10), TUBB2B (n = 8) or TUBB3 (n = 5) were studied by a brain MRI scan performed either on a 1.5 T (n = 10) or 3 T (n = 18) MR scanner with focus on the posterior fossa. RESULTS: Cerebellar anomalies were detected in 24/28 patients (86%). CD was recognised in 19/28 (68%) including cortical cerebellar dysplasia (CCD) in 18/28, either involving only the cerebellar hemispheres (12/28) or associated with vermis dysplasia (6/28). CCD was located only in the right hemisphere in 13/18 (72%), including four TUBB2B-, four TUBB3- and five TUBA1A-mutated patients, while in the other five TUBA1A cases it was located only in the left hemisphere or in both hemispheres. The postero-superior region of the cerebellar hemispheres was most frequently affected. CONCLUSIONS: The cerebellar involvement in tubulinopathies shows specific features that may be labelled as 'tubulin-related CD'. This pattern is unique and differs from other genetic causes of cerebellar dysplasia. KEY POINTS: • Cortical cerebellar dysplasia without cysts is suggestive of tubulin-related disorder. • Cerebellar dysplasia in tubulinopathies shows specific features labelled as 'tubulin-related CD'. • Focal and unilateral involvement of cerebellar hemispheres has important implications for counselling.

Longitudinal volumetric and 2D assessment of cerebellar atrophy in a large cohort of children with phosphomannomutase deficiency (PMM2-CDG).

OBJECTIVE: We aim to delineate the progression of cerebellar atrophy (the primary neuroimaging finding) in children with phosphomannomutase-deficiency (PMM2-CDG) by analyzing longitudinal MRI studies and performing cerebellar volumetric analysis and a 2D cerebellar measurement. METHODS: Statistical analysis was used to compare MRI measurements [midsagittal vermis relative diameter (MVRD) and volume] of children with PMM2-CDG and sex- and age-matched controls, and to determine the rate of progression of cerebellar atrophy at different ages. RESULTS: Fifty MRI studies of 33 PMM2-CDG patients were used for 2D evaluation, and 19 MRI studies were available for volumetric analysis. Results from a linear regression model showed that patients have a significantly lower MVRD and cerebellar volume compared to controls (p < 0.001 and p < 0.001 respectively). There was a significant negative correlation between age and MVRD for patients (p = 0.014). The rate of cerebellar atrophy measured by the loss of MVRD and cerebellar volume per year was higher at early ages (r = -0.578, p = 0.012 and r = -0.323, p = 0.48 respectively), particularly in patients under 11 years (p = 0.004). There was a significant positive correlation between MVRD and cerebellar volume in PMM2-CDG patients (r = 0.669, p = 0.001). CONCLUSIONS: Our study quantifies a progression of cerebellar atrophy in PMM2-CDG patients, particularly during the first decade of life, and suggests a simple and reliable measure, the MVRD, to monitor cerebellar atrophy. Quantitative measurement of MVRD and cerebellar volume are essential for correlation with phenotype and outcome, natural follow-up, and monitoring in view of potential therapies in children with PMM2-CDG.

Sensitivity of susceptibility-weighted imaging in detecting developmental venous anomalies and associated cavernomas and microhemorrhages in children.

PURPOSE: Developmental venous anomalies (DVA) are common neuroimaging abnormalities that are traditionally diagnosed by contrast-enhanced T1-weighted images as the gold standard. We aimed to evaluate the sensitivity of SWI in detecting DVA and associated cavernous malformations (CM) and microhemorrhages in children in order to determine if SWI may replace contrast-enhanced MRI sequences. METHODS: Contrast-enhanced T1-weighted images were used as diagnostic gold standard for DVA. The presence of DVA was qualitatively assessed on axial SWI and T2-weighted images by an experienced pediatric neuroradiologist. In addition, the presence of CM and microhemorrhages was evaluated on SWI and contrast-enhanced T1-weighted images. RESULTS: Fifty-seven children with DVA (34 males, mean age at neuroimaging 11.2 years, range 1 month to 17.9 years) were included in this study. Forty-nine out of 57 DVA were identified on SWI (sensitivity of 86%) and 16 out of 57 DVA were detected on T2-weighted images (sensitivity of 28.1%). General anesthesia-related changes in brain hemodynamics and oxygenation were most likely responsible for the majority of SWI false negative. CM were detected in 12 patients on axial SWI, but only in six on contrast-enhanced T1-weighted images. Associated microhemorrhages could be identified in four patients on both axial SWI and contrast-enhanced T1-weighted images, although more numerous and conspicuous on SWI. CONCLUSION: SWI can identify DVA and associated cavernous malformations and microhemorrhages with high sensitivity, obviating the need for contrast-enhanced MRI sequences.

The structural connectome in children: basic concepts, how to build it, and synopsis of challenges for the developing pediatric brain.

PURPOSE: The structural connectome is a comprehensive structural description of the network of elements and connections forming the brain. In recent years, this framework has progressively been used to investigate the pediatric brain. METHODS: We discuss the different steps and emphasize key technical aspects required for the successful reconstruction, analysis, and visualization of the pediatric structural connectome using current state-of-the-art neuroimaging and post-processing techniques. RESULTS: The two key components of structural connectome are a node (a cortical region obtained with high-resolution anatomical imaging) and an edge (structural association between cortical regions, defined with tractography). After delineation of nodes and edges, an association matrix can be generated by compiling all pairwise associations between nodes and applying a threshold to produce a binary adjacency matrix. Several measures can be used to characterize the topological architecture of the brain's networks. Finally, we provide an overview of various visualization methods of the structural connectome in children. CONCLUSION: The human connectome is the culmination of more than a century of conceptual and methodological innovation. Biological substrates of brain development such as cortical gyration and myelination challenge the acquisition, reconstruction, and analysis of structural connectome in children and require specific considerations compared to adults.

Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes.

BACKGROUND: Ciliopathies are an extensive group of autosomal recessive or X-linked disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. The aim of this study is to describe the mutational frequency and phenotypic spectrum of the CEP120 gene. METHODS: Exome sequencing was performed in 145 patients with Joubert syndrome (JS), including 15 children with oral-facial-digital syndrome type VI (OFDVI) and 21 Meckel syndrome (MKS) fetuses. Moreover, exome sequencing was performed in one fetus with tectocerebellar dysraphia with occipital encephalocele (TCDOE), molar tooth sign and additional skeletal abnormalities. As a parallel study, 346 probands with a phenotype consistent with JS or related ciliopathies underwent next-generation sequencing-based targeted sequencing of 120 previously described and candidate ciliopathy genes. RESULTS: We present six probands carrying nine distinct mutations (of which eight are novel) in the CEP120 gene, previously found mutated only in Jeune asphyxiating thoracic dystrophy (JATD). The CEP120-associated phenotype ranges from mild classical JS in four patients to more severe conditions in two fetuses, with overlapping features of distinct ciliopathies that include TCDOE, MKS, JATD and OFD syndromes. No obvious correlation is evident between the type or location of identified mutations and the ciliopathy phenotype. CONCLUSION: Our findings broaden the spectrum of phenotypes caused by CEP120 mutations that account for nearly 1% of patients with JS as well as for more complex ciliopathy phenotypes. The lack of clear genotype-phenotype correlation highlights the relevance of comprehensive genetic analyses in the diagnostics of ciliopathies.

Cystic cerebellar dysplasia and biallelic LAMA1 mutations: a lamininopathy associated with tics, obsessive compulsive traits and myopia due to cell adhesion and migration defects.

BACKGROUND: Laminins are heterotrimeric complexes, consisting of α, ß and γ subunits that form a major component of basement membranes and extracellular matrix. Laminin complexes have different, but often overlapping, distributions and functions. METHODS: Under our clinical protocol, NCT00068224, we have performed extensive clinical and neuropsychiatric phenotyping, neuroimaging and molecular analysis in patients with laminin α1 (LAMA1)-associated lamininopathy. We investigated the consequence of mutations in LAMA1 using patient-derived fibroblasts and neuronal cells derived from neuronal stem cells. RESULTS: In this paper we describe individuals with biallelic mutations in LAMA1, all of whom had the cerebellar dysplasia, myopia and retinal dystrophy, in addition to obsessive compulsive traits, tics and anxiety. Patient-derived fibroblasts have impaired adhesion, reduced migration, abnormal morphology and increased apoptosis due to impaired activation of Cdc42, a member of the Rho family of GTPases that is involved in cytoskeletal dynamics. LAMA1 knockdown in human neuronal cells also showed abnormal morphology and filopodia formation, supporting the importance of LAMA1 in neuronal migration, and marking these cells potentially useful tools for disease modelling and therapeutic target discovery. CONCLUSION: This paper broadens the phenotypes associated with LAMA1 mutations. We demonstrate that LAMA1 deficiency can lead to alteration in cytoskeletal dynamics, which may invariably lead to alteration in dendrite growth and axonal formation. Estimation of disease prevalence based on population studies in LAMA1 reveals a prevalence of 1-20 in 1 000 000. TRIAL REGISTRATION NUMBER: NCT00068224.

Novel Contrast-Enhanced Ultrasound Evaluation in Neonatal Hypoxic Ischemic Injury: Clinical Application and Future Directions.

Sensitive, specific, and safe bedside evaluation of brain perfusion is key to the early diagnosis, treatment, and improved survival of neonates with hypoxic ischemic injury. Contrast-enhanced ultrasound (US) imaging is a novel imaging technique in which intravenously injected gas-filled microbubbles generate enhanced US echoes from an acoustic impedance mismatch. This article describes contrast-enhanced US imaging in 2 neonates with hypoxic ischemic injury and future directions on developing quantitative contrast-enhanced US techniques for improved characterization of perfusion abnormalities. The importance of studying the temporal evolution of brain perfusion in neonatal hypoxic ischemic injury is also highlighted.

Radiological findings of abnormalities associated with congenital Zika virus infection: conclusions from World Radiology Day 2016.

In July 2015, Brazil reported an association between Zika virus infection and Guillain-Barre syndrome, and then in October 2015, between Zika and microcephaly. Most countries and territories in the Region of the Americas were later affected by the virus, creating a public health emergency. Each year, the Pan American Health Organization (PAHO), Regional Office of the World Health Organization commemorates World Radiology Day (WRD), which highlights the role of radiology in public health. In 2016, PAHO devoted its WRD efforts to the Zika infection. Experts and partners presented and discussed the various radiological findings of Zika infection, the crucial role of obstetric ultrasound in the screening and monitoring of abnormalities associated with confirmed Zika virus infection, and the appropriateness of utilizing other neuroimaging technologies to study brain abnormalities in neonates and infants with prenatal Zika virus infection. The conclusions of WRD 2016 recommend that upon confirmation, prenatal ultrasound be used as the main tool to investigate and monitor suspected cases, with subsequent multidisciplinary postnatal assessments that include neuropediatric clinical studies and relevant neuroimaging. Additionally, radiology technicians should be adequately trained and a quality assurance program should be implemented to ensure timely, safe, and accurate diagnosis.

En julio del 2015, Brasil informó una asociación entre la infección por el virus del Zika y el síndrome de Guillain-Barré y luego, en octubre 2015, entre la infección por el virus del Zika y la microcefalia. Posteriormente, la mayoría de los países y territorios de la Región de las Américas se vio afectada por el virus, lo que dio lugar a una emergencia de salud pública. Todos los años, la Organización Panamericana de la Salud (OPS), la Oficina Regional de la Organización Mundial de la Salud, conmemora el Día Mundial de la Radiología, en el que se reconoce la importancia de la radiología en la salud pública. En el 2016, la OPS dedicó las actividades en el marco del Día Mundial de la Radiología a la infección por el virus del Zika. Diversos expertos y asociados presentaron los distintos signos radiográficos de la infección por el virus del Zika, y debatieron sobre esto, así como sobre el papel fundamental que desempeñan las ecografías obstétricas en el tamizaje y el seguimiento de las anomalías asociadas con la infección por el virus del Zika confirmada, y sobre la pertinencia de utilizar técnicas de neurodiagnóstico por imágenes para estudiar las anomalías cerebrales en recién nacidos y lactantes con infección por el virus del Zika prenatal. Las conclusiones del Día Mundial de la Radiología del 2016 recomiendan que, tras la confirmación de la infección, se utilicen las ecografías prenatales como herramienta principal para investigar y hacer un seguimiento de los casos presuntos, seguida por una evaluación posnatal multidisciplinaria en la que se incluyan estudios clínicos neuropediátricos y las técnicas de neurodiagnóstico por imágenes pertinentes. Además, se debe capacitar adecuadamente a los técnicos de radiología y se debe ejecutar un programa de garantía de la calidad para asegurar el diagnóstico oportuno, seguro y certero.

Em julho de 2015, o Brasil informou existir associação entre a infecção por vírus zika e síndrome de Guillain-Barré e, em outubro do mesmo ano, entre o vírus zika e microcefalia. A maioria de países e territórios na Região das Américas foi subsequentemente afetada pelo vírus, constituindo emergência de saúde pública. Todos os anos, a Organização Pan-Americana da Saúde (OPAS), Escritório Regional da Organização Mundial da Saúde (OMS) comemora o Dia Internacional da Radiologia destacando o papel da radiologia em saúde pública. Em 2016, a OPAS dedicou este dia à infecção por vírus zika. Especialistas e parceiros apresentaram e debateram os diversos achados radiológicos na infecção por vírus zika, o papel fundamental do exame de ultrassom obstétrico na detecção precoce e monitoramento de anomalias associadas à infecção confirmada e quando convém usar outras técnicas de neuroimagem para estudar as anomalias cerebrais nos recém-nascidos e lactentes com infecção pré-natal. O painel do Dia Internacional da Radiologia 2016 recomenda que, com a confirmação da infecção, o ultrassom pré-natal seja o principal método usado para investigar e monitorar os casos suspeitos, com subsequente avaliação pósnatal multidisciplinar incluindo estudos clínicos neuropediátricos e exames de neuroimagem. Além disso, o pessoal técnico em radiologia deve ser adequadamente capacitado e implantado um programa de garantia da qualidade para assegurar o diagnóstico preciso, seguro e oportuno.

Case 236: Middle Interhemispheric Variant of Holoprosencephaly.

History A 13-year-old girl presented for evaluation and further management of spastic diplegia cerebral palsy. Absence of the corpus callosum was noted at screening prenatal head ultrasonography. She was born at full term via spontaneous vaginal delivery. Physical examination revealed decreased axial muscle tone and increased muscle tone in her extremities; the latter was more severe. She was nonambulatory. No midline craniofacial anomaly was seen. She had dysarthria but was able to speak in full sentences. She was in sixth grade with an individualized education program. She had mild behavioral problems, such as "acting out" in school. Brain magnetic resonance (MR) imaging, including three-dimensional T1- and T2-weighted sequences, was performed without intravenous administration of contrast material to evaluate the brain.

Diffusion tensor imaging: A biomarker of outcome in Krabbe's disease.

Krabbe's disease is a rare autosomal recessive lysosomal disorder resulting from deficiency of ß-galactocerebrosidase that affects primarily cerebral white matter and peripheral nerves. Conventional magnetic resonance imaging (MRI) is sensitive to changes in white matter myelination, but its assessment is based purely on qualitative, visual inspection, and it is subject to interobserver variability and open to reader bias. Diffusion tensor imaging (DTI) is an advanced MRI technique that provides quantitative information about the microscopic structural organization of the white matter and changes in cell density and myelination, and it is a suitable MRI tool for studying Krabbe's disease. This Review discusses the available studies on the application of quantitative DTI analysis to assess white matter changes in patients with Krabbe's disease. Quantitative analysis of DTI scalars, especially radial diffusivity and fractional anisotropy, has been shown to be a sensitive in vivo biomarker of white matter microstructural damage in Krabbe's disease, to detect early white matter injury in asymptomatic neonates with Krabbe's disease, to predict motor and cognitive functions after hematopoietic stem cell transplantation (HSCT), and to serve as a measurement for monitoring effects of HSCT on white matter development in Krabbe's disease. © 2016 Wiley Periodicals, Inc.

Pre- and Postnatal Neuroimaging of Congenital Cerebellar Abnormalities.

The human cerebellum has a protracted development that makes it vulnerable to a broad spectrum of developmental disorders including malformations and disruptions. Starting from 19 to 20 weeks of gestation, prenatal magnetic resonance imaging (MRI) can reliably study the developing cerebellum. Pre- and postnatal neuroimaging plays a key role in the diagnostic work-up of congenital cerebellar abnormalities. Diagnostic criteria for cerebellar malformations and disruptions are based mostly on neuroimaging findings. The diagnosis of a Dandy-Walker malformation is based on the presence of hypoplasia, elevation, and counterclockwise upward rotation of the cerebellar vermis and cystic dilatation of the fourth ventricle, which extends posteriorly filling out the posterior fossa. For the diagnosis of Joubert syndrome, the presence of the molar tooth sign (thickened, elongated, and horizontally orientated superior cerebellar peduncles and an abnormally deep interpeduncular fossa) is needed. The diagnostic criteria of rhombencephalosynapsis include a complete or partial absence of the cerebellar vermis and continuity of the cerebellar hemispheres across the midline. Unilateral cerebellar hypoplasia is defined by the complete aplasia or hypoplasia of one cerebellar hemisphere. Familiarity with these diagnostic criteria as well as the broad spectrum of additional neuroimaging findings is important for a correct pre- and postnatal diagnosis. A correct diagnosis is essential for management, prognosis, and counseling of the affected children and their family.