Diffusion magnetic resonance imaging assessment of regional white matter maturation in preterm neonates.

PURPOSE: Diffusion magnetic resonance imaging (dMRI) studies report altered white matter (WM) development in preterm infants. Neurite orientation dispersion and density imaging (NODDI) metrics provide more realistic estimations of neurite architecture in vivo compared with standard diffusion tensor imaging (DTI) metrics. This study investigated microstructural maturation of WM in preterm neonates scanned between 25 and 45 weeks postmenstrual age (PMA) with normal neurodevelopmental outcomes at 2 years using DTI and NODDI metrics. METHODS: Thirty-one neonates (n = 17 male) with median (range) gestational age (GA) 32+1 weeks (24+2-36+4) underwent 3 T brain MRI at median (range) post menstrual age (PMA) 35+2 weeks (25+3-43+1). WM tracts (cingulum, fornix, corticospinal tract (CST), inferior longitudinal fasciculus (ILF), optic radiations) were delineated using constrained spherical deconvolution and probabilistic tractography in MRtrix3. DTI and NODDI metrics were extracted for the whole tract and cross-sections along each tract to assess regional development. RESULTS: PMA at scan positively correlated with fractional anisotropy (FA) in the CST, fornix and optic radiations and neurite density index (NDI) in the cingulum, CST and fornix and negatively correlated with mean diffusivity (MD) in all tracts. A multilinear regression model demonstrated PMA at scan influenced all diffusion measures, GA and GAxPMA at scan influenced FA, MD and NDI and gender affected NDI. Cross-sectional analyses revealed asynchronous WM maturation within and between WM tracts.). CONCLUSION: We describe normal WM maturation in preterm neonates with normal neurodevelopmental outcomes. NODDI can enhance our understanding of WM maturation compared with standard DTI metrics alone.

Invited Review: Factors associated with atypical brain development in preterm infants: insights from magnetic resonance imaging.

Preterm birth (PTB) is a leading cause of neurodevelopmental and neurocognitive impairment in childhood and is closely associated with psychiatric disease. The biological and environmental factors that confer risk and resilience for healthy brain development and long-term outcome after PTB are uncertain, which presents challenges for risk stratification and for the discovery and evaluation of neuroprotective strategies. Neonatal magnetic resonance imaging reveals a signature of PTB that includes dysconnectivity of neural networks and atypical development of cortical and deep grey matter structures. Here we provide a brief review of perinatal factors that are associated with the MRI signature of PTB. We consider maternal and foetal factors including chorioamnionitis, foetal growth restriction, socioeconomic deprivation and prenatal alcohol, drug and stress exposures; and neonatal factors including co-morbidities of PTB, nutrition, pain and medication during neonatal intensive care and variation conferred by the genome/epigenome. Association studies offer the first insights into pathways to adversity and resilience after PTB. Future challenges are to analyse quantitative brain MRI data with collateral biological and environmental data in study designs that support causal inference, and ultimately to use the output of such analyses to stratify infants for clinical trials of therapies designed to improve outcome.

Machine-learning to characterise neonatal functional connectivity in the preterm brain.

Brain development is adversely affected by preterm birth. Magnetic resonance image analysis has revealed a complex fusion of structural alterations across all tissue compartments that are apparent by term-equivalent age, persistent into adolescence and adulthood, and associated with wide-ranging neurodevelopment disorders. Although functional MRI has revealed the relatively advanced organisational state of the neonatal brain, the full extent and nature of functional disruptions following preterm birth remain unclear. In this study, we apply machine-learning methods to compare whole-brain functional connectivity in preterm infants at term-equivalent age and healthy term-born neonates in order to test the hypothesis that preterm birth results in specific alterations to functional connectivity by term-equivalent age. Functional connectivity networks were estimated in 105 preterm infants and 26 term controls using group-independent component analysis and a graphical lasso model. A random forest-based feature selection method was used to identify discriminative edges within each network and a nonlinear support vector machine was used to classify subjects based on functional connectivity alone. We achieved 80% cross-validated classification accuracy informed by a small set of discriminative edges. These edges connected a number of functional nodes in subcortical and cortical grey matter, and most were stronger in term neonates compared to those born preterm. Half of the discriminative edges connected one or more nodes within the basal ganglia. These results demonstrate that functional connectivity in the preterm brain is significantly altered by term-equivalent age, confirming previous reports of altered connectivity between subcortical structures and higher-level association cortex following preterm birth.

Whole-brain mapping of structural connectivity in infants reveals altered connection strength associated with growth and preterm birth.

Cerebral white-matter injury is common in preterm-born infants and is associated with neurocognitive impairments. Identifying the pattern of connectivity changes in the brain following premature birth may provide a more comprehensive understanding of the neurobiology underlying these impairments. Here, we characterize whole-brain, macrostructural connectivity following preterm delivery and explore the influence of age and prematurity using a data-driven, nonsubjective analysis of diffusion magnetic resonance imaging data. T1- and T2-weighted and -diffusion MRI were obtained between 11 and 31 months postconceptional age in 49 infants, born between 25 and 35 weeks postconception. An optimized processing pipeline, combining anatomical, and tissue segmentations with probabilistic diffusion tractography, was used to map mean tract anisotropy. White-matter tracts where connection strength was related to age of delivery or imaging were identified using sparse-penalized regression and stability selection. Older children had stronger connections in tracts predominantly involving frontal lobe structures. Increasing prematurity at birth was related to widespread reductions in connection strength in tracts involving all cortical lobes and several subcortical structures. This nonsubjective approach to mapping whole-brain connectivity detected hypothesized changes in the strength of intracerebral connections during development and widespread reductions in connectivity strength associated with premature birth.

The effects of hemorrhagic parenchymal infarction on the establishment of sensori-motor structural and functional connectivity in early infancy.

INTRODUCTION: The objective of the study was to characterize alterations of structural and functional connectivity within the developing sensori-motor system in infants with focal perinatal brain injury and at high risk of cerebral palsy. METHODS: Functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) data were used to study the developing functional and structural connectivity framework in six infants born prematurely at term equivalent age. This was first characterised in three infants without focal pathology, which was then compared to that derived from three infants with unilateral haemorrhagic parenchymal infarction and a subsequent focal periventricular white matter lesion who developed later haemiparesis. RESULTS: Functional responses to passive hand movement were in the contralateral perirolandic cortex, regardless of focal pathology. In infants with unilateral periventricular injury, afferent thalamo-cortical tracts appeared to have developed compensatory trajectories which circumvented areas of damage. In contrast, efferent corticospinal tracts showed marked asymmetry at term equivalent age following focal brain injury. Sensori-motor network analysis suggested that inter-hemispheric functional connectivity is largely preserved despite pathology and that impairment may be associated with adverse neurodevelopmental outcome. CONCLUSION: Following focal perinatal brain injury, altered structural and functional connectivity is already present and can be characterized with MRI at term equivalent age. The results of this small case series suggest that these techniques may provide valuable new information about prognosis and the pathophysiology underlying cerebral palsy.

A Uniform Description of Perioperative Brain MRI Findings in Infants with Severe Congenital Heart Disease: Results of a European Collaboration.

BACKGROUND AND PURPOSE: A uniform description of brain MR imaging findings in infants with severe congenital heart disease to assess risk factors, predict outcome, and compare centers is lacking. Our objective was to uniformly describe the spectrum of perioperative brain MR imaging findings in infants with congenital heart disease. MATERIALS AND METHODS: Prospective observational studies were performed at 3 European centers between 2009 and 2019. Brain MR imaging was performed preoperatively and/or postoperatively in infants with transposition of the great arteries, single-ventricle physiology, or left ventricular outflow tract obstruction undergoing cardiac surgery within the first 6 weeks of life. Brain injury was assessed on T1, T2, DWI, SWI, and MRV. A subsample of images was assessed jointly to reach a consensus. RESULTS: A total of 348 MR imaging scans (180 preoperatively, 168 postoperatively, 146 pre- and postoperatively) were obtained in 202 infants. Preoperative, new postoperative, and cumulative postoperative white matter injury was identified in 25%, 30%, and 36%; arterial ischemic stroke, in 6%, 10%, and 14%; hypoxic-ischemic watershed injury in 2%, 1%, and 1%; intraparenchymal cerebral hemorrhage, in 0%, 4%, and 5%; cerebellar hemorrhage, in 6%, 2%, and 6%; intraventricular hemorrhage, in 14%, 6%, and 13%; subdural hemorrhage, in 29%, 17%, and 29%; and cerebral sinovenous thrombosis, in 0%, 10%, and 10%, respectively. CONCLUSIONS: A broad spectrum of perioperative brain MR imaging findings was found in infants with severe congenital heart disease. We propose an MR imaging protocol including T1-, T2-, diffusion-, and susceptibility-weighted imaging, and MRV to identify ischemic, hemorrhagic, and thrombotic lesions observed in this patient group.

A common neonatal image phenotype predicts adverse neurodevelopmental outcome in children born preterm.

Diffuse white matter injury is common in preterm infants and is a candidate substrate for later cognitive impairment. This injury pattern is associated with morphological changes in deep grey nuclei, the localization of which is uncertain. We test the hypotheses that diffuse white matter injury is associated with discrete focal tissue loss, and that this image phenotype is associated with impairment at 2years. We acquired magnetic resonance images from 80 preterm infants at term equivalent (mean gestational age 29(+6)weeks) and 20 control infants (mean GA 39(+2)weeks). Diffuse white matter injury was defined by abnormal apparent diffusion coefficient values in one or more white matter region (frontal, central or posterior white matter at the level of the centrum semiovale), and morphological difference between groups was calculated from 3D images using deformation based morphometry. Neurodevelopmental assessments were obtained from preterm infants at a mean chronological age of 27.5months, and from controls at a mean age of 31.1months. We identified a common image phenotype in 66 of 80 preterm infants at term equivalent comprising: diffuse white matter injury; and tissue volume reduction in the dorsomedial nucleus of the thalamus, the globus pallidus, periventricular white matter, the corona radiata and within the central region of the centrum semiovale (t=4.42 p<0.001 false discovery rate corrected). The abnormal image phenotype is associated with reduced median developmental quotient (DQ) at 2years (DQ=92) compared with control infants (DQ=112), p<0.001. These findings indicate that specific neural systems are susceptible to maldevelopment after preterm birth, and suggest that neonatal image phenotype may serve as a useful biomarker for studying mechanisms of injury and the effect of putative therapeutic interventions.

Somatosensory cortical activation identified by functional MRI in preterm and term infants.

Functional MRI (fMRI) has not previously been used systematically to investigate brain function in preterm infants. We here describe statistically robust and reproducible fMRI results in this challenging subject group using a programmable somatosensory stimulus synchronized with MR image acquisition which induced well-localized positive blood oxygen level dependent (BOLD) responses contralateral to the side of the stimulation in: 11 preterm infants (median post menstrual age 33 weeks and 4 days, range 29+1 to 35+3); 6 control infants born at term gestational age; and 18 infants born preterm (median gestational age at birth 30 weeks and 5 days, range 25+4 to 36+0) but studied at term corrected gestational age. Bilateral signals were identified in 8 of the ex-preterm infants at term age. Anatomical confirmation of appropriate activations was provided with diffusion tensor imaging (DTI) based tractography which identified connecting pathways from the regions of activation through the ipsilateral corticospinal tracts and posterior limb of the internal capsule. These results demonstrate that it is possible to reliably identify positive BOLD signals in the infant brain and that fMRI techniques can also be applied in the study of preterm infants.

Early postnatal maternal trait anxiety is associated with the behavioural outcomes of children born preterm <33 weeks.

Maternal ante- and postnatal anxiety have been associated with children's socio-emotional development. Moreover, maternal anxiety has been studied as both a contributing factor and consequence of preterm birth, and children born preterm are more likely to develop behavioural problems compared to term-born controls. This study investigated the association between maternal anxiety measured soon after birth and mental health in 215 ex-preterm children, born at <33 weeks, who participated in the Evaluation of Preterm Imaging Study. Children were followed-up at a median age of 4.6 years (range 4.2-6.6), and received behavioural and cognitive evaluation. Maternal trait anxiety was assessed with the Spielberger State-Trait Anxiety Index at term corrected age. Primary outcome measures were children's Strengths and Difficulties Questionnaire (SDQ) and Social Responsiveness Scale 2 (SRS-2) scores, indicative of generalised psychopathology and autism symptomatology, respectively. IQ was assessed with the Wechsler Preschool and Primary Scales of Intelligence. The final sample, after excluding participants with missing data and multiple pregnancy (n = 75), consisted of 140 children (51.4% male). Results showed that increased maternal trait anxiety at term corrected age was associated with children's higher SDQ scores (ß = 0.25, 95% CI 0.09-0.41, p = 0.003, f2 = 0.08) and SRS-2 scores (ß = 0.15, 95% CI 0.02-0.28, p = 0.03, f2 = 0.04). Our findings indicate that children born preterm whose mothers are more anxious in the early postnatal period may show poorer mental health outcomes at pre-school age. Further research is needed to investigate preventative measures that can be offered to high-risk premature babies and their families.

MRI Findings at Term-Corrected Age and Neurodevelopmental Outcomes in a Large Cohort of Very Preterm Infants.

BACKGROUND AND PURPOSE: Brain MR imaging at term-equivalent age is a useful tool to define brain injury in preterm infants. We report pragmatic clinical radiological assessment of images from a large unselected cohort of preterm infants imaged at term and document the spectrum and frequency of acquired brain lesions and their relation to outcomes at 20 months. MATERIALS AND METHODS: Infants born at <33 weeks' gestation were recruited from South and North West London neonatal units and imaged in a single center at 3T at term-equivalent age. At 20 months' corrected age, they were invited for neurodevelopmental assessment. The frequency of acquired brain lesions and the sensitivity, specificity, and negative and positive predictive values for motor, cognitive, and language outcomes were calculated, and corpus callosal thinning and ventricular dilation were qualitatively assessed. RESULTS: Five hundred four infants underwent 3T MR imaging at term-equivalent age; 477 attended for assessment. Seventy-six percent of infants had acquired lesions, which included periventricular leukomalacia, hemorrhagic parenchymal infarction, germinal matrix-intraventricular hemorrhage, punctate white matter lesions, cerebellar hemorrhage, and subependymal cysts. All infants with periventricular leukomalacia, and 60% of those with hemorrhagic parenchymal infarction had abnormal motor outcomes. Routine 3T MR imaging of the brain at term-equivalent age in an unselected preterm population that demonstrates no focal lesion is 45% sensitive and 61% specific for normal neurodevelopment at 20 months and 17% sensitive and 94% specific for a normal motor outcome. CONCLUSIONS: Acquired brain lesions are common in preterm infants routinely imaged at term-equivalent age, but not all predict an adverse neurodevelopmental outcome.

Brain cell membrane motion-restricted phospholipids: a cerebral 31-phosphorus magnetic resonance spectroscopy study of patients with schizophrenia.

This study directly assessed, for the first time, whether there was a change in brain cell motion-restricted membrane phospholipids in vivo in patients with schizophrenia with mild to moderate negative symptoms, by quantification of the underlying broad resonance signal of cerebral 31-phosphorus magnetic resonance scans. Cerebral 31-phosphorus magnetic resonance spectroscopy was carried out in 16 schizophrenia patients and 16 age- and gender-matched normal controls. Spectra were obtained from 70x70x70 mm3 voxels using an image-selected in vivo spectroscopy pulse sequence. There was no significant difference in the broad resonances between the two groups, with the mean (S.E.) percentage signal being 59.4 (5.6) for the patients and 53.5 (5.9) for the controls. The phosphomonoesters and phosphodiesters narrow signals also did not differ significantly, their ratio being 0.26 (0.01) in the patients and 0.25 (0.01) in the controls. These results appear to be at variance with the changes expected under the membrane phospholipid hypothesis of schizophrenia.

Negative correlation between cerebral inorganic phosphate and the volumetric niacin response in male patients with schizophrenia who have seriously and dangerously violently offended: a (31)P magnetic resonance spectroscopy study.

The aim of the study was to examine the association of arachidonic acid-related signal transduction with cerebral metabolism in patients with schizophrenia who have violently and dangerously offended while psychotic. Cerebral 31-phosphorus magnetic resonance spectroscopy was carried out in 11 male patients with schizophrenia who had violently offended (homicide, attempted murder, or wounding with intent to cause grievous bodily harm) while psychotic. Spectra were obtained from 70 x 70 x 70 mm(3) voxels using an image-selected in vivo spectroscopy pulse sequence. Niacin flush testing results were quantified as the volumetric niacin response. There was a strong, and negative, correlation between the volumetric niacin response and the metabolite concentration of inorganic phosphate expressed as a ratio of the total 31-phosphorus signal (p<0.005). Our results suggest that patients with schizophrenia who have violently offended and have poor phospholipid-related signal transduction may have higher levels of cerebral energy metabolism.

Smaller cerebellar volumes in very preterm infants at term-equivalent age are associated with the presence of supratentorial lesions.

BACKGROUND AND PURPOSE: Traditionally cerebellar functions are thought to be related to control of tone, posture, gait, and coordination of skilled motor activity. However, there is an increasing body of evidence implicating the cerebellum in cognition, language, memory, and motor learning. Preterm infants are at increased risk of neurodevelopmental delay, cognitive dysfunction, and behavioral and emotional disturbances. The role of the cerebellum in these adverse outcomes is unclear. OBJECTIVE: The objective of this study was to determine whether absolute cerebellar volumes differ between term-equivalent preterm infants and term-born control infants and to assess whether cerebellar volume is influenced by any possible antenatal, perinatal, and postnatal factors. METHODS: The study compared the MR imaging cerebellar volume by using a manual quantification program of 113 preterm infants at term-equivalent age and 15 term-born control infants. RESULTS: The median cerebellar volume of preterm at term-equivalent age was 25.4 cm3 and that of term-born control infants was 26.9 cm3. On initial analysis, there was a significant median difference of 2.0 cm3 (95% CI, 1.2 cm3 to 2.7 cm3) (2-sided P < .0001). However multiple regression analysis of perinatal variables showed that only infants with supratentorial lesions (P = .003) were significantly associated with the reduction in cerebellar volumes. The median cerebellar volumes were the following: supratentorial lesions, 18.9 cm3; no supratentorial lesions, 26.1 cm3; and term infants, 26.9 cm3 (analysis of variance, P < .0001). Hence, there was no significant difference in cerebellar volumes of preterm infants at term-equivalent age in the absence of supratentorial lesions. The median vermal volumes were 0.7 cm3 and were significantly related to cerebellar volumes both in preterm infants with and without lesions and in term-control infants. CONCLUSION: Premature infants at term-equivalent age have similar total cerebellar and vermal volumes compared with term infants in the presence of normal brain imaging. Reduced cerebellar volume in preterm infants at term-equivalent age is seen in association with supratentorial pathology such as hemorrhagic parenchymal infarction, intraventricular hemorrhage with dilation, and periventricular leukomalacia.

Altered white matter and cortical structure in neonates with antenatally diagnosed isolated ventriculomegaly.

Ventriculomegaly (VM) is the most common central nervous system abnormality diagnosed antenatally, and is associated with developmental delay in childhood. We tested the hypothesis that antenatally diagnosed isolated VM represents a biological marker for altered white matter (WM) and cortical grey matter (GM) development in neonates. 25 controls and 21 neonates with antenatally diagnosed isolated VM had magnetic resonance imaging at 41.97(± 2.94) and 45.34(± 2.14) weeks respectively. T2-weighted scans were segmented for volumetric analyses of the lateral ventricles, WM and cortical GM. Diffusion tensor imaging (DTI) measures were assessed using voxel-wise methods in WM and cortical GM; comparisons were made between cohorts. Ventricular and cortical GM volumes were increased, and WM relative volume was reduced in the VM group. Regional decreases in fractional anisotropy (FA) and increases in mean diffusivity (MD) were demonstrated in WM of the VM group compared to controls. No differences in cortical DTI metrics were observed. At 2 years, neurodevelopmental delays, especially in language, were observed in 6/12 cases in the VM cohort. WM alterations in isolated VM cases may be consistent with abnormal development of WM tracts involved in language and cognition. Alterations in WM FA and MD may represent neural correlates for later neurodevelopmental deficits.

Unsuspected pulmonary tuberculosis in a community teaching hospital.

Tuberculosis remains a significant clinical and public health problem in the United States. To determine if a significant proportion of hospitalized patients diagnosed as having pulmonary tuberculosis were not suspected of the disease following initial patient assessment, we retrospectively reviewed the microbiology records of a 515-bed community teaching hospital and identified all patients with culture-proven Mycobacterium tuberculosis infection hospitalized between January 1983 and December 1987. Pulmonary tuberculosis was not suspected in 13 (42%) of 31 patients with active disease. These patients were elderly (92% aged 65 years or older vs 8% aged less than 65 years), had a delay in respiratory isolation (6 vs 1 days) and diagnosis (8 vs 3 days), in addition to a longer hospitalization (16 vs 11 days) with increased mortality (46% vs 11%). Inadequate diagnosis may contribute to the persistence of morbidity and mortality from tuberculosis in this country.

Neonatal arthrogryposis and absent limb muscles: a muscle developmental gene defect?

We describe a child who presented at birth with arthrogryposis. Following a muscle biopsy a diagnosis of congenital muscular dystrophy was made and a skin biopsy 12 years later confirmed the presence of merosin. Her clinical picture was unusual, however, for merosin-positive congenital muscular dystrophy. She had extreme wasting and weakness of her arms and legs. In contrast, she had good neck and trunk control, and no facial or respiratory muscle weakness. We have used magnetic resonance imaging to examine the pattern of muscle involvement in this case. No recognizable muscle could be identified in the limbs. In contrast, the axial muscles were preserved. This striking pattern of virtual absence of muscles in the limbs with sparing of the axial muscle suggests that a gene responsible for the migration and/or proliferation of limb muscle precursor cells may be involved in the disease process. It is recognized that merosin-positive congenital muscular dystrophy is a heterogeneous disease. Magnetic resonance imaging is a useful tool for examining in detail the pattern of muscle involvement and identifying individual phenotypes. Understanding more about which muscles are affected in children with congenital myopathies may provide information on the underlying pathological process and help in the search for candidate proteins and genes.

Early white matter changes on brain magnetic resonance imaging in a newborn affected by merosin-deficient congenital muscular dystrophy.

In 1996 we reported sequential magnetic resonance imaging study in an infant with merosin-deficient congenital muscular dystrophy with normal brain magnetic resonance imaging at 3 weeks and white matter changes by 6 months. We now report an infant with merosin-deficient congenital muscular dystrophy with a mild degree of white matter changes already present on brain magnetic resonance imaging at 5 days of age. The difference may be due to a difference in the T2 sequences used. The images in this present case were obtained with a fast spin echo sequence (echo time: 210 ms). The increased T2 weighted may be responsible for a better detection of the white matter changes at an early stage, when they can be missed on conventional, less weighting T2 sequences. These results suggest that, by using appropriate sequences, mild white matter changes may be detectable on brain magnetic resonance imaging in the first days of life in infants with merosin-deficient congenital muscular dystrophy.

Cognitive abilities in children with congenital muscular dystrophy: correlation with brain MRI and merosin status.

The aim of the study was to evaluate whether children with merosin-positive or merosin-deficient congenital muscular dystrophy (CMD) show any cognitive impairment and whether this is related to brain abnormalities on magnetic resonance imaging (MRI). Twenty-two patients (age range: 5.8-15.3 years) were assessed by the Wechsler Intelligence Scales. Twelve were merosin-positive and ten merosin-deficient. One child had severe mental retardation and could not be tested. The full scale IQ in the remaining 21 ranged from 51 to 134, the verbal IQ ranged from 78 to 136 and the performance from 51 to 136. Of the twelve children with normal merosin one had a mild delay (IQ < 75) and two were borderline (IQ 75-95). Of the ten children with merosin-deficiency, one showed severe mental retardation and could not be tested, one showed a mild delay and two had borderline results. While the children with merosin deficiency with the typical diffuse white matter changes on MRI had normal scores, the children who in addition had cerebellar hypoplasia had lower performance IQ. The child with cortical dysplasia had severe mental retardation. Our results suggest that the spectrum of cognitive abilities in CMD is very wide even within genetically homogeneous conditions.

Muscle magnetic resonance imaging in patients with congenital muscular dystrophy and Ullrich phenotype.

The aim of this study was to evaluate muscle magnetic resonance imaging findings in patients with congenital muscular dystrophy and Ullrich phenotype. Fifteen children with congenital muscular dystrophy and Ullrich phenotype were included in the study. All patients had collagen VI studies in muscle and, when family structure was informative, linkage studies to the collagen 6 loci. Three of the 15 patients had reduced collagen in muscle. One of the three was from an informative family and linked to one of the collagen 6 loci. Another patient was linked to one of the collagen 6 loci but had normal expression of collagen in muscle. The remaining 11 all had normal collagen expression in muscle. Only two of these 11 were from informative families and linkage to collagen 6 loci was excluded in them. All patients had muscle magnetic resonance imaging of their leg muscles using transverse T1 sequences. With the exception of the two patients in whom linkage to the collagen 6 loci was excluded, the other 13 patients showed the same pattern of selective involvement on magnetic resonance imaging of thigh muscles. This consisted of relative sparing of sartorius, gracilis, adductor longus and rectus. This pattern was also found in the case linked COL6A1/A2 locus but with normal collagen. This finding, and the striking clinical and magnetic resonance imaging concordance between patients with normal and reduced collagen VI in muscle suggest that collagen VI could still be the culprit in several cases with normal collagen expression, or alternatively a primary defect in a protein that closely interacts with collagen VI. Mutation analysis of the collagen 6 genes in cases with normal collagen VI expression is needed to resolve this issue.

Head growth in infants with hypoxic-ischemic encephalopathy: correlation with neonatal magnetic resonance imaging.

OBJECTIVES: The aims of the study were to establish the relationship between head growth in the first year of life with the pattern on injury on neonatal magnetic resonance imaging (MRI) in infants with hypoxic-ischemic encephalopathy (HIE) and to relate these to the neurodevelopmental outcome. METHODS: Fifty-two term infants who presented at birth with a neonatal encephalopathy consistent with HIE and who had neonatal brain MRI were entered into the study. Head circumference charts were evaluated retrospectively and the head growth over the first year of life compared with the pattern of brain lesions on MRI and with the neurodevelopmental outcome at 1 year of age. Suboptimal head growth was classified as a drop of >2 standard deviations across the percentiles with or without the development of microcephaly, which was classified as a head circumference below the third percentile. RESULTS: There was no statistical difference between the neonatal head circumferences of the infants presenting with HIE and control infants. At 12 months, microcephaly was present in 48% of the infants with HIE, compared with 3% of the controls. Suboptimal head growth was documented in 53% of the infants with HIE, compared with 3% of the controls. Suboptimal head growth was significantly associated with the pattern of brain lesions, in particular to involvement of severe white matter and to severe basal ganglia and thalamic lesions. Suboptimal head growth predicted abnormal neurodevelopmental outcome with a sensitivity of 79% and a specificity of 78%, compared with the presence of microcephaly at 1 year of age, which had a sensitivity of only 65% and a specificity of 73%. The exceptions were explained by infants with only moderate white matter abnormalities who had suboptimal head growth but normal outcome at 1 year of age and by infants with moderate basal ganglia and thalamic lesions only who had normal head growth but significant motor abnormality.