Extracerebral Space Research Articles

Clinical and genetic analysis of a child with West syndrome due to a de novo variant of NEXMIF gene

To investigate the clinical features and genetic variant of a child with West syndrome due to a variant of NEXMIF gene. A child who was admitted to the First Medical Center of Chinese PLA General Hospital in March 2021 was selected as the study subject. Clinical data of the patient was collected. The child and his parents were subjected to whole exome sequencing. Candidate variant was verified by Sanger sequencing and pathogenicity analysis. The child, a 4-month-old boy, had presented with spastic seizures with no obvious cause. Abnormal EEG, severe hypsarrhythmia, and multiple spastic seizures were discovered. Cranial MRI revealed widening of the extracerebral space at the top of the frontal lobe. Physical examination revealed that the child could not hold his head up, and could not respond to sounds or follow objects with his eyes. He also has microcephaly, with height < 1 s. The child was diagnosed with West syndrome at a local hospital, and was given prednisone orally for 3 months, with seizures under control. Topiramate tablets were taken orally for maintenance treatment, and he has been seizure-free for 7 months. DNA sequencing revealed that he has harbored a de novo nonsense variant of c.982_c.983delTT (p.L328Dfs*23) in the NEXMIF gene. For children with West syndrome with severe developmental delay or even regression as the first symptoms, uncontrollable seizures and abnormal facial appearance, mutations of the NEXMIF gene should be suspected, and genetic testing can facilitate early diagnosis and treatment.

Clinical and electroencephalogram characteristics of methylmalonic acidemia with MMACHC and MUT gene mutations

ObjectiveThis study investigated the clinical, imaging, and electroencephalogram (EEG) characteristics of methylmalonic acidemia (MMA) with nervous system damage as the primary manifestation.MethodsFrom January 2017 to November 2022, patients with nervous system injury as the main clinical manifestation, diagnosed with methylmalonic acidemia by metabolic and genetic testing, were enrolled and analyzed. Their clinical, imaging, and electroencephalogram data were analyzed.ResultsA total of 18 patients were enrolled, including 15 males and 3 females. The clinical symptoms were convulsions, poor feeding, growth retardation, disorder of consciousness, developmental delay, hypotonia, and blood system changes. There were 6 cases (33%) of hydrocephalus, 9 (50%) of extracerebral space widened, 5 (27%) of corpus callosum thinning, 3 (17%) of ventricular dilation, 3 (17%) of abnormal signals in the brain parenchyma (frontal lobe, basal ganglia region, and brain stem), and 3 (17%) of abnormal signals in the lateral paraventricular. In addition, there were 3 cases (17%) of cerebral white matter atrophy and 1 (5%) of cytotoxic edema in the basal ganglia and cerebral peduncle. EEG data displayed 2 cases (11%) of hypsarrhythmia, 3 (17%) of voltage reduction, 12(67%) of abnormal discharge, 13 (72%) of abnormal sleep physiological waves or abnormal sleep structure, 1 (5%) of immature (delayed) EEG development, and 8 (44%) of slow background. There were 2 cases (11%) of spasms, 1 (5%) of atonic seizures, and 1 (5%) of myoclonic seizures. There were 16 patients (89%) with hyperhomocysteinemia. During follow-up, 1 patient was lost to follow-up, and 1 died. In total, 87.5% (14/16) of the children had varying developmental delays. EEG was re-examined in 11 cases, of which 8 were normal, and 3 were abnormal. Treatments included intramuscular injections of vitamin B12, L-carnitine, betaine, folic acid, and oral antiepileptic therapy. Acute treatment included anti-infective, blood transfusion, fluid replacement, and correcting acidosis. The other treatments included low-protein diets and special formula milk powder.ConclusionMethylmalonic acidemia can affect the central nervous system, leading to structural changes or abnormal signals on brain MRI. Metabolic screening and genetic testing help clarify the diagnosis. EEG can reflect changes in brain waves during the acute phase.

Clinical phenotypes of developmental and epileptic encephalopathy-related recurrent KCNH5 missense variant p.R327H in Chinese children

KCNH5 gene encodes for the voltage-gated potassium channel protein Kv10.2. Here, we investigated the clinical features of developmental and epileptic encephalopathy (DEE) in five Chinese pediatric patients with a missense mutation (p.R327H) in KCNH5 gene. These patients had undergone video EEG to evaluate background features and epileptiform activity, as well as 3.0 T MRI scans for structural analysis and intelligence assessments using the Gesell Developmental Observation or Wechsler Intelligence Scale for Children. Seizure onset occurs between 4 and 10 months of age, with focal and generalized tonic-clonic seizures being common. Initial EEG findings showed multiple multifocal sharp waves, sharp slow waves or spike slow waves, and spike waves. Brain MRI revealed widened extracerebral space in only one patient. Mechanistically, the KCNH5 mutation disrupts the two hydrogen bonds between Arg327 and Asp304 residues, potentially altering the protein’s structural stability and function. Almost 80 % of patients receiving add-on valproic acid (VPA) therapy experienced a reduction in epileptic seizure frequency. Altogether, this study presents the first Chinese cohort of pediatric DEE patients with the KCNH5 p.R327H mutation, highlighting focal seizures as the predominant seizure type and incomplete mutation penetrance. Add-on VPA therapy was likely effective in the early stages of DEE pathogenesis.

Phenotypes in children with GNAO1 encephalopathy in China.

The GNAO1 gene encodes the α-subunit (Gαo) of the heterotrimeric guanine nucleotide-binding protein (G protein). The aim of this study was to explore the clinical characteristics of patients with GNAO1 pathogenic variations. Ten patients with pathogenic variations in GNAO1 were enrolled from the Shenzhen Children's Hospital. Clinical data from several cases previously reported from China were also included and analyzed. Twenty-seven patients with variations in GNAO1 were analyzed (10 patients from Shenzhen Children's Hospital, 17 patients from previously published studies) including 12 boys and 15 girls. The median age of onset was 3 months with moderate to severe global developmental delay. Nineteen different GNAO1 heterozygous variants were identified. Epilepsy was observed in 18 patients (67%, 18/27), movement disorder (MD) was observed in 22 patients (81%, 22/27), and both were seen in 13 patients (48%, 13/27). Seizures typically presented as focal seizures in all patients with epilepsy. MD typically presented as dystonia and chorea. Loss-of-function (LOF) or partial loss-of-function (PLOF) mutations were more frequent in patients with developmental and epileptic encephalopathy (p = 0.029). Interictal electroencephalograms showed multifocal or diffuse epileptiform discharges. The most common magnetic resonance imaging finding was widened extracerebral space. In contrast to MD, in which improvements were not common, seizures were easily controlled by anti-seizure medications. Severe dystonia in three patients was effectively treated by deep brain stimulation. Seven (26%, 7/27) patients died of respiratory complications, status dystonicus, choreoathetosis, or sudden unexpected death in epilepsy. We analyzed clinical data of 27 cases of GNAO1-related encephalopathy in China. MD seemed to be the central feature and was most difficult to control. LOF or PLOF variants were significantly associated with developmental and epileptic encephalopathy. The active intervention of severe dystonia may prevent death due to status dystonicus. However, future studies with larger samples are needed to confirm these results.

Clinical and functional study of two de novo variations of CDKL5 gene.

The cyclin-dependent kinase like 5 (CDKL5) gene variation is X-linked dominant and is associated with type 2 developmental and epileptic encephalopathy (DEE). Although numerous cases of CDKL5 have been reported, there is limited discussion regarding functional verification. We described two children with DEE caused by de novo variations of CDKL5 gene, analyzed their clinical manifestations, and performed genetic testing on their gene variation sites. The two cases presented with tonic seizures followed by epileptic spasms, indicative of refractory epilepsy. Physical examination revealed abnormal facial features, including wide eye distance, low nose base, and high nose bridge. Both cases exhibited developmental disabilities. Cranial magnetic resonance imaging (MRI) showed widening of the bilateral frontotemporal extracerebral space. Genetic testing identified variations at the gene sites c.463 + 4A > G (splicing) and c.1854_1861delCAAAGTGA (p.D618Efs*18). Minigene experiments further confirmed that the intronic variation c.463 + 4A > G (splicing) disrupted splicing, leading to protein truncation. CDKL5 gene variation can lead to DEE, and intron variation site c.463 + 4A > G (splicing) can cause protein truncation, which is a pathogenic variation.

Neurological and endocrinological involvement in neonatal lupus erythematosus: a retrospective study at a tertiary hospital in Eastern China.

Neonatal lupus erythematosus (NLE) is a rare autoimmune disease that causes transient impairment of multi-organ functions and is mainly caused by maternally transmitted antibodies. This study aims to investigate the clinical features of infants with NLE, focusing on the presence of neurological and endocrinological involvement. The clinical data of infants diagnosed with NLE at the Children's Hospital of Soochow University from 2011 to 2022 were collected and retrospectively analyzed. In all, 39 patients with NLE were included, and the most common symptom was rash, followed by hematological, hepatic, cardiac, gastrointestinal, neurological, and endocrine symptoms. Among the 10 patients with neurological impairment, intracranial hemorrhage was the most common, followed by convulsions, hydrocephalus, extracerebral space enlargement, and aseptic meningitis. All patients with neurological impairment were positive for anti-SSA/Ro antibodies. Five of these patients were double positive for anti-SSA/Ro and anti-SSB/La antibodies. All 10 patients had multi-organ system involvement, with hematological involvement being the most common, and three patients had varying degrees of developmental delay at the post-discharge follow-up. Nine patients with endocrine impairment were positive for anti-SSA/Ro antibodies, with pancreatic impairment being the most common. There were four cases of hyperinsulinemia and hypoglycemia, one case of diabetes mellitus with ketoacidosis, two cases of hypothyroidism, one case of hypoadrenocorticism, and one case of lysinuric protein intolerance, all of which were normalized before discharge. All patients with endocrine impairment showed hematological involvement, and some showed feeding intolerance as their first symptom. One patient had abnormal liver function at post-discharge follow-up, and two patients had a rash caused by a severe allergy to milk protein. At our hospital, no significant gender differences were observed in the occurrence of NLE, and a predominance of skin, blood, liver, and heart involvement was observed. Patients with multiple central nervous system injuries and organ involvement are more likely to have growth retardation. Endocrine disorders are transient in NLE patients, and some showed feeding intolerance as the first manifestation. Key Points •A retrospective investigation of the clinical characteristics and prognosis of 39 NLE patients was performed, focusing on the clinical features of patients with neurological and endocrine system involvement to improve clinicians' understanding of this disease.

Neurodevelopmental outcomes in premature infants with very low and extremely low birth weight at two years corrected age

Premature infants born before 32 weeks of gestation with very low and extremely low birth weights are at higher risk for several neurodevelopmental disorders, including cerebral palsy and sensory, cognitive, and behavioral problems. The more complications are observed in the neonatal period, the higher is the likelihood of long-term complications of prematurity. Studying the factors that influence the outcome of neurological development is the only way to develop better treatment approaches.Purpose. Assessment of correlations between the brain ultrasonography data in children with very low and extremely low birth weights at birth with perinatal and neonatal risk factors, to predict neurodevelopmental outcomes and neuropsychic disorders at 2 years of corrected age.Material and methods. The material of the study was premature babies with very low and extremely low birth weights (≤32 weeks, ≤1500 g) who were born and received treatment and care in two large perinatal centers in Yerevan. Neurodevelopmental outcome in children was assessed using the Bayley-III developmental scale at 2 years of age.Results. 64% of ex-premature babies had completely normal development. 10% had cerebral palsy, 21% of children had a speech delay, 5% developed mental deficiency. Socio-emotional and behavioral problems were more common, especially in the social and practical areas (27% and 25%, respectively). 85.7% of children with motor disorders and 60% of children with speech delay had concomitant behavioral disorders. Deviations in behavior were found in 34.4% of children with normal (mental, motor, speech) development. More than 9% of children had very good results, 2% had a high level of mental development, and 3% — a high level of motor development.Conclusion. Predictors for the development of motor disorders and cerebral palsy were Grade 2 and 3 intraventricular hemorrhages, cystic periventricular leukomalacia, ventriculomegaly. Ventriculomegaly at term equivalent age, expansion of the extracerebral space and interhemispheric fissure led to combination of cerebral palsy and delayed speech development.

A novel de novo frameshift variation in the SON gene causing severe global developmental delay and seizures in a Chinese female.

With the rapid development of genetic detection technology, especially next-generation sequencing, identification of the aetiology of unexplained intellectual disabilities accompanied by seizures and other dysmorphic features has become possible. The purpose of our paper is to make a definitive diagnosis of a girl with neonatal hypotonia, severe global developmental delay, seizures and mild facial dysmorphism. The clinical data of the patient were retrospectively studied. Whole-exome sequencing was performed on a blood sample from the patient. Subsequently, Sanger sequencing was utilized for validation of variants and parental validation. The patient had hypotonia since the neonatal period. She showed a significant delay in physical and psychomotor development. She did not have any speech until the age of 2years and 6months. She had seizures that were easy to control with levetiracetam. The craniocerebral magnetic resonance imaging (MRI) then showed mild delayed myelination, enlarged bilateral ventricles and widened frontotemporal extracerebral space. Interictal video electroencephalogram (VEEG) was normal. She had esotropia and mild facial abnormalities with a flat nasal bridge and a short nose. She showed no abnormalities in the heart, genitourinary or skeletal systems. Whole-exome sequencing revealed a novel de novo variant c.5334_5335delAG (p. Arg1778Serfs*11) in the SON gene. Our paper reports a novel variant in the SON gene and provides a definitive diagnosis of a female with neonatal hypotonia, severe global developmental delay, seizures and mild facial abnormalities, which are symptoms consistent with Zhu-Tokita-Takenouchi-Kim syndrome (ZTTK syndrome).

Supratentorial Brain Metrics Predict Neurodevelopmental Outcome in Very Preterm Infants without Brain Injury at Age 2 Years

Introduction: Very preterm infants are at risk for adverse neurodevelopmental outcome. To better identify children without brain injury at risk for developmental sequelae, we assessed predictive values of supratentorial brain metrics in relation to outcome. Methods: Very preterm infants underwent magnetic resonance imaging (MRI) at term-equivalent age. Infants with any grade of supra- or infratentorial brain injury according to Kidokoro et al. [Pediatrics 2014;134:e444–53] were excluded. Supratentorial brain metrics (biparietal width, extracerebral space, interhemispheric distance) were measured and categorised using existing cut-off values. The Psychomotor Developmental Index (PDI) and Mental Developmental Index (MDI) were assessed using the Bayley Scales of Infant Development, second and third edition, at 2 years of age. Developmental delay was defined as a score <85. Positive and negative predictive values for developmental delay were calculated. Results: A total of 237 very preterm infants were enrolled. Of all infants, 59 (21.2%) showed developmental delay. Infants with z-scores less than –0.5 for biparietal width had significantly lower PDI (p = 0.039) and MDI (p = 0.042) than infants with normal z-scores. Enlargement of extracerebral spaces was also related to lower PDI (p = 0.047) and MDI (p = 0.036). Negative predictive value was highest when all brain metrics were within the normal range (PDI <85: 96.6%, MDI <85: 90.0%). Combining the biparietal width and the interhemispheric distance showed highest positive predictive values for developmental delay (MDI or PDI <85: 58.3%). Discussion: Supratentorial brain metrics are predictive for neurodevelopmental outcome in infants with ostensibly normal MRI. A combination of supratentorial brain metrics is most meaningful for identifying infants at risk for long-term sequelae.

Novel CDKL5 mutations were found in patients in China: retrospective investigation in cases of CDKL5-related disorders

ObjectiveCDKL5-related disorders (CDD) is an epileptic encephalopathy resulted of gene mutations of CDKL5. This study aimed to explore the development process of CDD and to expand its mutation spectrum.MethodsClinic datawas collected about three infantile epileptic encephalopathy cases diagnosed at Xinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine. Next generation sequencing technology was used to find three de novo mutations of CDKL5. We searched published literatures about CDKL5 in pubmed and made an analysis about our clinic data and the related literatures.ResultsThe three patients were all girls. Their average onset age of seizures was around 2 months, and all of them have intractable epileptic seizures, severe intellectual disability, and hypotension. Among them, two presented infantile spasm and high arrhythmia in EEG, and the other manifested clonic seizure and broad epileptiform discharge in EEG. Extracerebral space widening in cranial MRIs was demonstrated in two cases. Visual evoked potential was abnormal in two cases. Seizures were resistant to all kinds of antiepileptic drugs (AEDs). Gene tests showed three de novo mutations of CDKL5: one was a truncated mutation (c.2254A > T,P.R752X, stop279), which was pathogenic according to the ACMG guide, the other two were missense mutations (c.377G > T,p.Cys126Phe) and a frameshift mutation (c.362-362insG(p.Ala122GlyfsTer7), which were likely pathogenic according to the ACMG.ConclusionsAll three de novo mutations are first reported. Based on the combined related literature and the manifestations observed, we diagnosed the three children as CDKL5-related disorders, and concluded that the de novo CDKL5 mutations are the reason for their epilepsy.

Characteristic MR Imaging Findings of the Neonatal Brain in RASopathies.

Neuroimaging features in neonates with RASopathies are rarely reported, and to date, there are no neuroimaging studies conducted in this population. Our aim was to investigate the occurrence of supratentorial and posterior fossa abnormalities on brain MRIs of neonates with a RASopathy. An observational case-control study of neonates with a confirmed RASopathy was conducted. The presence of an intraventricular and/or parenchymal hemorrhage and punctate white matter lesions and assessments of the splenium of the corpus callosum, gyrification of the cortical gray matter, and enlargement of the extracerebral space were noted. The vermis height, transverse cerebellar diameter, cranial base angle, tentorial angle, and infratentorial angle were measured. We reviewed 48 brain MR studies performed at 3 academic centers in 3 countries between 2009 and 2017. Sixteen of these infants had a genetically confirmed RASopathy (group 1), and 32 healthy infants were enrolled as the control group (group 2). An increased rate of white matter lesions, extracerebral space enlargement, simplification of the cortical gyrification, and white matter abnormalities were seen in group 1 (P < .001, for each). The vermis height of patients was significantly lower, and tentorial and infratentorial angles were significantly higher in group 1 (P = .01, P < .001, and P = .001, respectively). Neonates with a RASopathy had characteristic structural and acquired abnormalities in the cortical gray matter, white matter, corpus callosum, cerebellum, and posterior fossa. This study provides novel neuroimaging findings on supratentorial and posterior fossa abnormalities in neonates with a RASopathy.

Clinical and imaging characteristics in neonatal refractory purulent meningitis

Objective To identify the clinical and imaging characteristics in neonatal refractory purulent meningitis. Methods Clinical data of 70 cases of neonatal purulent meningitis admitted to the neonatal intensive care unit at Children's Hospital of Fudan University from January, 2009 to December, 2014 were reviewed retrospectively. The patients were divided into refractory group (n=28) and non-refractory group (n=42) according to the course of antimicrobial therapy. The clinical and brain MRI characteristics of neonatal refractory purulent meningitis were analyzed. Parameters were compared between the two groups using Chi-square or Fisher's exact tests, and Wilcoxon tests where appropriate. Risk factors of neonatal refractory purulent meningitis were investigated by univariate and multivariate Logistic regression analysis. Results Among the 70 cases, 31(44.3%) were positive for cerebrospinal fluid (CSF)/blood culture. The positive rate was higher in the refractory group than in the non-refractory group [75.0% (21/28) vs 23.8% (10/42), χ2=17.843, P<0.01]. The most common pathogenic bacteria isolated in the refractory group were Escherichia coli [8 cases (38.1%)] and group B streptococci [5 cases (23.8%)]. Compared to the non-refractory group, patients in the refractory group were more likely to have seizure, higher CSF white blood cell count, higher CSF protein concentration and lower CSF glucose concentration [53.6%(15/28) vs 7.1% (3/42), 965.0 (463.0-2 200.0)×106/L vs 116.5 (61.0-327.5)×106/L, 3 221.1(2 354.3-4 633.5) mg/L vs 1 487.6(988.2-1 924.1) mg/L, and 0.2 (0.1-0.8) mmol/L vs 1.5 (1.2-1.8) mmol/L; all P<0.01]. Multivariate Logistic regression analysis showed that seizure, low CSF glucose concentration on admission, and a positive CSF/blood culture result neonatal refractory purulent meningitis (OR=9.6, 95%CI: 1.2-76.0; OR=15.0, 95%CI: 5.6-63.3; and OR=7.3, 95%CI: 1.5-36.0, respectively). Abnormal brain MRI findings, including intracranial extracerebral space abnormality, ventricular dilatation and periventricular white matter injury, were more common in the refractory group [100.0%(28/28) vs 61.9%(26/42), χ2=13.827 totally; 64.3%(18/28) vs 21.4%(9/42), χ2=13.023 for intracranial extracerebral space abnormality; 60.7%(17/28) vs 19.0%(8/42), χ2=12.704 for ventricular dilation and 28.6%(8/28) vs 2.4%(1/42) for periventricular white matter injury; all P <0.01]. Compared with the non-refractory group, the refractory group had a longer hospital stay [(48.0±17.4) d vs (26.0±10.2) d, t=6.016, P<0.01] and more adverse events [67.9%(19/28) vs 31.0%(13/42), χ2=9.220, P=0.002], including hearing impairment and requirement of neurosurgical intervention [14/18 ears vs 10/46 ears (21.7%), χ2=4.292, P=0.038]. There was no death in both groups during hospitalization. Conclusions Neonates with seizure, low CSF glucose concentration and positive CSF/blood culture results are more likely to have refractory purulent meningitis. Brain MRI abnormalities are more common in neonatal refractory purulent meningitis. Key words: Meningitis, bacterial; Magnetic resonance imaging

以轻度胃肠炎起病的婴幼儿惊厥临床分析

目的：回顾内蒙古自治区人民医院儿科以轻度胃肠炎起病的婴幼儿惊厥病例，分析其临床特点。方法：对临床以轻度胃肠炎起病，病程中出现惊厥的患儿52例(女孩33例，男孩19例)进行临床观察和分析，并且随访至少3月。结果：所有观察患儿起病年龄是4~30月，男女比例是1.74。其中单次惊厥42例，发生2次以上惊厥10例；惊厥发生时间在胃肠炎起病平均2.37天；病人平均就诊次数为1.81次；全部病例进行脑电图检查，其中脑电图异常8例；全部病例中的48例(92.31%)进行了头颅影像学检查，头颅CT检查22例，头颅MRI检查26例，头颅CT检查均正常，仅3例在头颅MRI检查中发现轻度的脑外间隙增宽，轮状病毒抗体阳性20例(38.46%)。所有病例随访3~6月，再次惊厥1例。结论：婴幼儿期的轻度胃肠炎需警惕惊厥发生，大多预后良好。 Purpose: To analyze the electroclinical features with mild gastroenteritis onset benign infantile convulsions from the Inner Mongolia Autonomous Region People’s Hospital. Methods: We re-viewed and analyzed the medical records of 52 patients (33 females and 19 males) diagnosed with mild gastroenteritis onset benign infantile convulsions and followed-up for at least 3 months. Results: The age of onset was 4 - 30 months and the female/male ratio was 1.74. There are 42 cases of single seizures, and 10 cases of multiple seizures. The average interval between the onset of gastroenteritis and seizures was 2.37 days. The average of the patients visit times was 1.81. Interictal electroencephalographic studies were accomplished in 52 patients. The EEG was abnormal in 8 patients (15.38%). Neuroimaging studies were accomplished in 48 patients (92.31%), cranial CT in 22 patients and MRI in 26 subjects. All CT results were normal. MRI results showed that 3 cases presented with an enlarged extra cerebral space in the temporal lobe. Rotavirus antigen was positive in stools in 20 cases (38.46%). Only 1 out of all patients suffered from recurrence of seizures during 3 - 6-month follow-up. Conclusions: The infant stage mild gastroenteritis needs to be mindful of convulsions. Most of the BICE’s prognosis is good.

Development of Cortical Morphology Evaluated with Longitudinal MR Brain Images of Preterm Infants.

IntroductionThe cerebral cortex develops rapidly in the last trimester of pregnancy. In preterm infants, brain development is very vulnerable because of their often complicated extra-uterine conditions. The aim of this study was to quantitatively describe cortical development in a cohort of 85 preterm infants with and without brain injury imaged at 30 and 40 weeks postmenstrual age (PMA).MethodsIn the acquired T2-weighted MR images, unmyelinated white matter (UWM), cortical grey matter (CoGM), and cerebrospinal fluid in the extracerebral space (CSF) were automatically segmented. Based on these segmentations, cortical descriptors evaluating volume, surface area, thickness, gyrification index, and global mean curvature were computed at both time points, for the whole brain, as well as for the frontal, temporal, parietal, and occipital lobes separately. Additionally, visual scoring of brain abnormality was performed using a conventional scoring system at 40 weeks PMA.ResultsThe evaluated descriptors showed larger change in the occipital lobes than in the other lobes. Moreover, the cortical descriptors showed an association with the abnormality scores: gyrification index and global mean curvature decreased, whereas, interestingly, median cortical thickness increased with increasing abnormality score. This was more pronounced at 40 weeks PMA than at 30 weeks PMA, suggesting that the period between 30 and 40 weeks PMA might provide a window of opportunity for intervention to prevent delay in cortical development.

Automatic segmentation of MR brain images of preterm infants using supervised classification

Preterm birth is often associated with impaired brain development. The state and expected progression of preterm brain development can be evaluated using quantitative assessment of MR images. Such measurements require accurate segmentation of different tissue types in those images.This paper presents an algorithm for the automatic segmentation of unmyelinated white matter (WM), cortical grey matter (GM), and cerebrospinal fluid in the extracerebral space (CSF). The algorithm uses supervised voxel classification in three subsequent stages. In the first stage, voxels that can easily be assigned to one of the three tissue types are labelled. In the second stage, dedicated analysis of the remaining voxels is performed. The first and the second stages both use two-class classification for each tissue type separately. Possible inconsistencies that could result from these tissue-specific segmentation stages are resolved in the third stage, which performs multi-class classification. A set of T1- and T2-weighted images was analysed, but the optimised system performs automatic segmentation using a T2-weighted image only.We have investigated the performance of the algorithm when using training data randomly selected from completely annotated images as well as when using training data from only partially annotated images. The method was evaluated on images of preterm infants acquired at 30 and 40weeks postmenstrual age (PMA). When the method was trained using random selection from the completely annotated images, the average Dice coefficients were 0.95 for WM, 0.81 for GM, and 0.89 for CSF on an independent set of images acquired at 30weeks PMA. When the method was trained using only the partially annotated images, the average Dice coefficients were 0.95 for WM, 0.78 for GM and 0.87 for CSF for the images acquired at 30weeks PMA, and 0.92 for WM, 0.80 for GM and 0.85 for CSF for the images acquired at 40weeks PMA. Even though the segmentations obtained using training data from the partially annotated images resulted in slightly lower Dice coefficients, the performance in all experiments was close to that of a second human expert (0.93 for WM, 0.79 for GM and 0.86 for CSF for the images acquired at 30weeks, and 0.94 for WM, 0.76 for GM and 0.87 for CSF for the images acquired at 40weeks).These results show that the presented method is robust to age and acquisition protocol and that it performs accurate segmentation of WM, GM, and CSF when the training data is extracted from complete annotations as well as when the training data is extracted from partial annotations only. This extends the applicability of the method by reducing the time and effort necessary to create training data in a population with different characteristics.

G193 Magnetic resonance imaging (mri) scans in children with neurodevelopmental disabilities: should a paediatric neuroradiologist’s opinion be sought?

Background At our local hospital MRI scans of children with developmental disabilities are reviewed by radiologists who provide the preliminary report. It is the choice of the treating paediatrician to seek further specialist paediatric neuroradiologist’s opinion. Aim Did differences in local and specialist opinion impact on diagnosis? Method Concurrent MRI scan reports of children with neurodisabilities from the local radiologist and the neuroradiologist were compared. Result 63 children had reports from local and specialist radiologist. All had neurodevelopmental difficulties from mild to severe range. The results were divided into three categories: Group 1: Where there was significant difference in opinion: 26 reports (41%) Periventricular leucomalacia (PVL) was detected in 11 of which 10 had spastic cerebral palsy. Other cases included the following: antenatal hypoxic Ischaemic encephalopathy (3), thinning or agenesis of corpus callosum (4), disorder of myelination (3). The specialist was more likely to detect disturbances of myelination, (delay, loss or degeneration) The specialist also ruled out (6%) white matter loss (3) and absent corpus callosum (1) reported by the local radiologist. Group 2: Where there was no difference in opinion: 29 reports (47%) The majority of these children (15) had global developmental delay without spasticity. Other cases included tonsilar herniation (2) Corpus callosum dysgenesis (2) hypoxic ischaemic encephalopathy (1) periventricular leucomalacia PVL (2), Cytomegalovirus infection (2) and hemisphere infarct (1) autism (2). Group 3: Only subtle differences in report which did not impact on diagnosis: 8 reports (13%) These included arachnoid cysts, aberrant patterns of myelination, age consistent delay in myelination and benign extra cerebral space enlargement. Conclusion This study showed that a paediatric neuroradiologist’s opinion is important and could impact on the diagnosis very significantly. They detected and ruled out abnormalities in 41% of cases resulting in conclusive diagnosis compatible with clinical findings. Periventricular leucomalacia (PVL) was more likely to be detected by the neuroradiologist and was the commonest finding contributing to clinical diagnosis. In children with global delay with no spasticity the reports were likely to be similar. Subtle white matter abnormalities were also more likely to be detected by the specialist.

Evaluation of automatic neonatal brain segmentation algorithms: the NeoBrainS12 challenge.

A number of algorithms for brain segmentation in preterm born infants have been published, but a reliable comparison of their performance is lacking. The NeoBrainS12 study (http://neobrains12.isi.uu.nl), providing three different image sets of preterm born infants, was set up to provide such a comparison. These sets are (i) axial scans acquired at 40 weeks corrected age, (ii) coronal scans acquired at 30 weeks corrected age and (iii) coronal scans acquired at 40 weeks corrected age. Each of these three sets consists of three T1- and T2-weighted MR images of the brain acquired with a 3T MRI scanner. The task was to segment cortical grey matter, non-myelinated and myelinated white matter, brainstem, basal ganglia and thalami, cerebellum, and cerebrospinal fluid in the ventricles and in the extracerebral space separately. Any team could upload the results and all segmentations were evaluated in the same way. This paper presents the results of eight participating teams. The results demonstrate that the participating methods were able to segment all tissue classes well, except myelinated white matter.

Moderate and late preterm birth: effect on brain size and maturation at term-equivalent age.

To compare the size of multiple brain structures, maturation in terms of both brain myelination and gyral development, and evidence of brain injury between moderate and late preterm (MLPT) and term-born infants at term-equivalent age. The study was approved by the human research ethics committees of the participating hospitals, and informed parental consent was obtained for all infants. One hundred ninety-nine MLPT and 50 term-born infants underwent 3-T magnetic resonance (MR) imaging brain examinations at 38-44 weeks of corrected gestational age. T1- and T2-weighted MR images were compared between groups for size of multiple cerebral structures, degree of myelination in the posterior limb of the internal capsule, gyral maturation, signal intensity abnormalities, and presence of cysts by a single assessor who was blinded to the gestational group and perinatal course of the infants. Group differences were compared by using linear regression for continuous variables and logistic regression for categorical variables, and interrater and intrarater reliability was assessed by using intraclass correlation coefficients. Compared with those in the term-born control group, measurements of brain biparietal diameter, corpus callosum, basal ganglia and thalami, and cerebellum were smaller in infants in the MLPT group (all P ≤ .01), while extracerebral space was larger (P < .0001). Myelination of the posterior limb of the internal capsule was less developed, and gyral maturation was delayed in the MLPT group (both P < .001). Signal intensity abnormalities and cysts were uncommon in both groups, with 13 (6.5%) MLPT infants and one (2%) term infant having abnormalities. Inter- and intrarater reliability was good for most measures, with intraclass correlation coefficients generally greater than 0.68. MLPT birth is associated with smaller brain size, less-developed myelination of the posterior limb of the internal capsule, and more immature gyral folding than those associated with full-term birth. These brain changes may form the basis of some of the long-term neurodevelopmental deficits observed in MLPT children. Online supplemental material is available for this article.

Automatic Segmentation of Eight Tissue Classes in Neonatal Brain MRI

PurposeVolumetric measurements of neonatal brain tissues may be used as a biomarker for later neurodevelopmental outcome. We propose an automatic method for probabilistic brain segmentation in neonatal MRIs.Materials and MethodsIn an IRB-approved study axial T1- and T2-weighted MR images were acquired at term-equivalent age for a preterm cohort of 108 neonates. A method for automatic probabilistic segmentation of the images into eight cerebral tissue classes was developed: cortical and central grey matter, unmyelinated and myelinated white matter, cerebrospinal fluid in the ventricles and in the extra cerebral space, brainstem and cerebellum. Segmentation is based on supervised pixel classification using intensity values and spatial positions of the image voxels. The method was trained and evaluated using leave-one-out experiments on seven images, for which an expert had set a reference standard manually. Subsequently, the method was applied to the remaining 101 scans, and the resulting segmentations were evaluated visually by three experts. Finally, volumes of the eight segmented tissue classes were determined for each patient.ResultsThe Dice similarity coefficients of the segmented tissue classes, except myelinated white matter, ranged from 0.75 to 0.92. Myelinated white matter was difficult to segment and the achieved Dice coefficient was 0.47. Visual analysis of the results demonstrated accurate segmentations of the eight tissue classes. The probabilistic segmentation method produced volumes that compared favorably with the reference standard. ConclusionThe proposed method provides accurate segmentation of neonatal brain MR images into all given tissue classes, except myelinated white matter. This is the one of the first methods that distinguishes cerebrospinal fluid in the ventricles from cerebrospinal fluid in the extracerebral space. This method might be helpful in predicting neurodevelopmental outcome and useful for evaluating neuroprotective clinical trials in neonates.

Cerebral volume at term age: Comparison between preterm and term-born infants using cranial ultrasound

Background and aimsVery preterm infants are at particular risk of neurodevelopmental impairments. This risk can be anticipated when major lesions are seen on cerebral ultrasound (cUS). However, most preterm infants do not have such lesions yet many have a relatively poor outcome. Our study aims were to describe a tri-dimensional cUS model for measuring cranial and brain volume and to determine the range of brain volumes found in preterm infants without major cUS lesions at term equivalent age (TEA) compared to term-born control infants. We also aimed to evaluate whether gestational age (GA) at birth or being small for gestational age (SGA) influenced estimated brain size. MethodsWe scanned a cohort of very preterm infants at TEA and term-born controls. Infants with major cerebral lesions were excluded. Measurements of intracranial diameters (bi-parietal, longitudinal, cranial height), brain structures, ventricles and extracerebral space (ECS) were made. A mathematical model was built to estimate from the cUS measurements the axial area and volumes of the cranium and brain. Appropriate statistical methods were used for comparisons; a p-value under 0.05 was considered significant. SGA infants from both groups were analysed separately. ResultsWe assessed 128 infants (72 preterms and 56 controls). The preterms' head was longer (11.5 vs. 10.5cm, p<0.001), narrower (7.8 vs. 8.4cm, p<0.001) and taller (8.9 vs. 8.6cm, p<0.01) than the controls'. Estimated intracranial volume was not statistically different between the groups (411 vs. 399cm3, NS), but preterms had larger estimated ECS volume (70 vs. 22cm3, p<0.001), lateral ventricular coronal areas (33 vs. 12mm2, p<0.001) and thalamo-occipital distances (20 vs. 16mm, p<0.001), but smaller estimated cerebral volume (340 vs. 377cm3, p<0.001). Smaller brain volumes were associated with being of lower gestational age and birth weight and being small-for-gestational age. ConclusionsWe have developed a model using cranial ultrasound for measuring cranial and brain volumes. Using this model our data suggest that even in the absence of major cerebral lesions, the average extrauterine cerebral growth of very preterm infants is compromised. Our model can help in identifying those preterm infants with smaller brains. Later follow-up data will determine the neurodevelopmental outcome of these preterm infants in relation to their estimated brain volumes.