The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders.

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics, and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals: the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%), and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%), and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%), and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P=0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%); motor delay with non-ambulance (64%); and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P=0.003), non-ambulance (P=0.035), ongoing enteral feeds (P<0.001), and cortical visual impairment (P=0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs; provide insights into their neurological basis; and, vitally, enable meaningful genetic counselling for affected individuals and their families.

Dysfunctional Postnatal Mitochondrial Energy Metabolism in a Patient with Neurodevelopmental Defects Caused by Intrauterine Growth Restriction Due to Idiopathic Placental Insufficiency.

We report the case of a four-year-old male patient with a complex medical history born prematurely as the result of intrauterine growth restriction due to placental insufficiency. His clinical manifestations included severe neurodevelopmental deficits, global developmental delay, Pierre-Robin sequence, and intractable epilepsy with both generalized and focal features. The proband's low levels of citrulline and lactic acidosis provoked by administration of Depakoke were evocative of a mitochondrial etiology. The proband's genotype-phenotype correlation remained undefined in the absence of nuclear and mitochondrial pathogenic variants detected by deep sequencing of both genomes. However, live-cell mitochondrial metabolic investigations provided evidence of a deficient oxidative-phosphorylation pathway responsible for adenosine triphosphate (ATP) synthesis, leading to chronic energy crisis in the proband. In addition, our metabolic analysis revealed metabolic plasticity in favor of glycolysis for ATP synthesis. Our mitochondrial morphometric analysis by transmission electron microscopy confirmed the suspected mitochondrial etiology, as the proband's mitochondria exhibited an immature morphology with poorly developed and rare cristae. Thus, our results support the concept that suboptimal levels of intrauterine oxygen and nutrients alter fetal mitochondrial metabolic reprogramming toward oxidative phosphorylation (OXPHOS) leading to a deficient postnatal mitochondrial energy metabolism. In conclusion, our collective studies shed light on the long-term postnatal mitochondrial pathophysiology caused by intrauterine growth restriction due to idiopathic placental insufficiency and its negative impact on the energy-demanding development of the fetal and postnatal brain.

Networks Underlie Temporal Onset of Dysplasia-Related Epilepsy: A MELD Study.

OBJECTIVE: The purpose of this study was to evaluate if focal cortical dysplasia (FCD) co-localization to cortical functional networks is associated with the temporal distribution of epilepsy onset in FCD. METHODS: International (20 center), retrospective cohort from the Multi-Centre Epilepsy Lesion Detection (MELD) project. Patients included if >3 years old, had 3D pre-operative T1 magnetic resonance imaging (MRI; 1.5 or 3 T) with radiologic or histopathologic FCD after surgery. Images processed using the MELD protocol, masked with 3D regions-of-interest (ROI), and co-registered to fsaverage_sym (symmetric template). FCDs were then co-localized to 1 of 7 distributed functional cortical networks. Negative binomial regression evaluated effect of FCD size, network, histology, and sulcal depth on age of epilepsy onset. From this model, predictive age of epilepsy onset was calculated for each network. RESULTS: Three hundred eighty-eight patients had median age seizure onset 5 years (interquartile range [IQR] = 3-11 years), median age at pre-operative scan 18 years (IQR = 11-28 years). FCDs co-localized to the following networks: limbic (90), default mode (87), somatomotor (65), front parietal control (52), ventral attention (32), dorsal attention (31), and visual (31). Larger lesions were associated with younger age of onset (p = 0.01); age of epilepsy onset was associated with dominant network (p = 0.04) but not sulcal depth or histology. Sensorimotor networks had youngest onset; the limbic network had oldest age of onset (p values <0.05). INTERPRETATION: FCD co-localization to distributed functional cortical networks is associated with age of epilepsy onset: sensory neural networks (somatomotor and visual) with earlier onset, and limbic latest onset. These variations may reflect developmental differences in synaptic/white matter maturation or network activation and may provide a biological basis for age-dependent epilepsy onset expression. ANN NEUROL 2022;92:503-511.

Clinical spectrum of orbital and ocular abnormalities on fetal MRI.

BACKGROUND: Fetal magnetic resonance imaging (MRI) may reveal sonographically occult ocular abnormalities. When discovered, acquired causes and genetic associations must be sought. OBJECTIVE: We aim to evaluate a fetal cohort with orbit and/or globe malformations to determine whether there are imaging patterns that suggest the underlying cause. MATERIALS AND METHODS: We searched all fetal MRI reports performed at an academic children's hospital over 9 consecutive years for orbit and/or globe abnormalities. Each positive exam and all follow-up MRIs were evaluated for interocular distance, globe size, shape and signal, and brain malformations. Genetic and clinical diagnoses were recorded from the medical record. RESULTS: Seventy-six of 3,085 fetuses (2.5%) were diagnosed with ocular and/or globe abnormalities; 50% had postnatal follow-up MR exams, all confirming the fetal MRI findings. Ninety-two percent (70/76) had concurrent brain malformations. Sixty-seven percent (51/76) were diagnosed with an underlying disorder and 39% of these were genetically proven. The most common diagnoses with ocular globe abnormalities included CHARGE (coloboma of the eye, heart anomaly, choanal atresia, retardation and genital and ear anomalies) syndrome, trisomy 13 syndrome, dystroglycanopathy, holoprosencephaly and diencephalic-mesencephalic junction dysplasia. Genetic diagnoses were more likely with ocular globe abnormalities than isolated orbital abnormalities (P=0.04). Sixty-seven percent of fetuses with ocular calcifications, hemorrhage and/or lens abnormalities had potential maternal risk factors (P=0.03). CONCLUSION: Malformed ocular globes are associated with brain malformations and genetic abnormalities. Ocular calcifications, hemorrhage and/or lens abnormalities may be associated with maternal risk factors. Genetic work-up should be considered when an ocular globe size or shape abnormality is detected.

Hippocampal rotation is associated with ventricular atrial size.

BACKGROUND: Fetal ventriculomegaly is a source of apprehension for expectant parents and may present prognostic uncertainty for physicians. Accurate prenatal counseling requires knowledge of its cause and associated findings as the differential diagnosis is broad. We have observed an association between ventriculomegaly and incomplete hippocampal inversion. OBJECTIVE: To determine whether ventricular size is related to incomplete hippocampal inversion. MATERIALS AND METHODS: We retrospectively evaluated pre- and postnatal brain MRIs in normal subjects (mean GA, 31 weeks; mean postnatal age, 27 days) and patients with isolated ventriculomegaly (mean GA, 31 weeks; mean postnatal age, 68 days) at a single academic medical center. Lateral ventricular diameter, multiple qualitative and quantitative markers of hippocampal inversion, and evidence of intraventricular hemorrhage were documented. RESULTS: Incomplete hippocampal inversion and ventricular size were associated in both normal subjects (n=51) and patients with ventriculomegaly (n=32) (P<0.05). Severe ventriculomegaly was significantly associated with adverse clinical outcome in postnatal (P=0.02) but not prenatal (P=0.43) groups. In all additional cases of isolated ventriculomegaly, clinical outcome was normal over the time of assessment (mean 1±1.9 years; range 0.01 to 10 years). CONCLUSION: Lateral ventricular atrial diameter and incomplete hippocampal inversion are associated. Less hippocampal inversion correlates with larger atria. For every 1-mm increase in fetal ventricular size, the odds of incomplete hippocampal inversion occurring increases by a factor of 1.6 in normal controls and 1.4 in patients with ventriculomegaly.

Fifteen years of urea cycle disorders brain research: Looking back, looking forward.

Urea cycle disorders (UCD) are inherited diseases resulting from deficiency in one of six enzymes or two carriers that are required to remove ammonia from the body. UCD may be associated with neurological damage encompassing a spectrum from asymptomatic/mild to severe encephalopathy, which results in most cases from Hyperammonemia (HA) and elevation of other neurotoxic intermediates of metabolism. Electroencephalography (EEG), Magnetic resonance imaging (MRI) and Proton Magnetic resonance spectroscopy (MRS) are noninvasive measures of brain function and structure that can be used during HA to guide management and provide prognostic information, in addition to being research tools to understand the pathophysiology of UCD associated brain injury. The Urea Cycle Rare disorders Consortium (UCDC) has been invested in research to understand the immediate and downstream effects of hyperammonemia (HA) on brain using electroencephalogram (EEG) and multimodal brain MRI to establish early patterns of brain injury and to track recovery and prognosis. This review highlights the evolving knowledge about the impact of UCD and HA in particular on neurological injury and recovery and use of EEG and MRI to study and evaluate prognostic factors for risk and recovery. It recognizes the work of others and discusses the UCDC's prior work and future research priorities.

Clinical 1H MRS in childhood neurometabolic diseases - part 2: MRS signatures.

Proton MRS of the brain provides the ability to gather direct information regarding the metabolic status of the brain at the time of MRI. Although selective vulnerability of brain tissue may yield distinct imaging patterns in neurometabolic disorders, it is not uncommon for the brain MRI to be normal, nonspecific, or show ambiguous abnormalities among several possible diagnoses, metabolic, or otherwise. This review highlights childhood neurometabolic diseases in which 1H MRS may show diagnostic or suggestive metabolic profiles without complicated acquisition or postprocessing techniques.

Clinical 1H MRS in childhood neurometabolic diseases-part 1: technique and age-related normal spectra.

Despite its vigorous ability to detect and measure metabolic disturbances, 1H MRS remains underutilized in clinical practice. MRS increases diagnostic yield and provides therapeutic measures. Because many inborn metabolic errors are now treatable, early diagnosis is crucial to prevent or curb permanent brain injury. Therefore, patients with known or suspected inborn metabolic errors stand to benefit from the addition of MRS. With education and practice, all neuroradiologists can perform and interpret MRS notwithstanding their training and prior experience. In this two-part review, we cover the requisite concepts for clinical MRS interpretation including technical considerations and normal brain spectral patterns based on age, location, and methodology.

COVID-19 pandemic ramifications on residential Smart homes energy use load profiles.

The COVID-19 pandemic has significantly affected people's behavioral patterns and schedules because of stay-at-home orders and a reduction of social interactions. Therefore, the shape of electrical loads associated with residential buildings has also changed. In this paper, we quantify the changes and perform a detailed analysis on how the load shapes have changed, and we make potential recommendations for utilities to handle peak load and demand response. Our analysis incorporates data from before and after the onset of the COVID-19 pandemic, from an Alabama Power Smart Neighborhood with energy-efficient/smart devices, using around 40 advanced metering infrastructure data points. This paper highlights the energy usage pattern changes between weekdays and weekends pre- and post-COVID-19 pandemic times. The weekend usage patterns look similar pre- and post-COVID-19 pandemic, but weekday patterns show significant changes. We also compare energy use of the Smart Neighborhood with a traditional neighborhood to better understand how energy-efficient/smart devices can provide energy savings, especially because of increased work-from-home situations. HVAC and water heating remain the largest consumers of electricity in residential homes, and our findings indicate an even further increase in energy use by these systems.

Image Quality Assessment of Fetal Brain MRI Using Multi-Instance Deep Learning Methods.

BACKGROUND: Due to random motion of fetuses and maternal respirations, image quality of fetal brain MRIs varies considerably. To address this issue, visual inspection of the images is performed during acquisition phase and after 3D-reconstruction, and the images are re-acquired if they are deemed to be of insufficient quality. However, this process is time-consuming and subjective. Multi-instance (MI) deep learning methods (DLMs) may perform this task automatically. PURPOSE: To propose an MI count-based DLM (MI-CB-DLM), an MI vote-based DLM (MI-VB-DLM), and an MI feature-embedding DLM (MI-FE-DLM) for automatic assessment of 3D fetal-brain MR image quality. To quantify influence of fetal gestational age (GA) on DLM performance. STUDY TYPE: Retrospective. SUBJECTS: Two hundred and seventy-one MR exams from 211 fetuses (mean GA ± SD = 30.9 ± 5.5 weeks). FIELD STRENGTH/SEQUENCE: T2 -weighted single-shot fast spin-echo acquired at 1.5 T. ASSESSMENT: The T2 -weighted images were reconstructed in 3D. Then, two fetal neuroradiologists, a clinical neuroscientist, and a fetal MRI technician independently labeled the reconstructed images as 1 or 0 based on image quality (1 = high; 0 = low). These labels were fused and served as ground truth. The proposed DLMs were trained and evaluated using three repeated 10-fold cross-validations (training and validation sets of 244 and 27 scans). To quantify GA influence, this variable was included as an input of the DLMs. STATISTICAL TESTS: DLM performance was evaluated using precision, recall, F-score, accuracy, and AUC values. RESULTS: Precision, recall, F-score, accuracy, and AUC averaged over the three cross validations were 0.85 ± 0.01, 0.85 ± 0.01, 0.85 ± 0.01, 0.85 ± 0.01, 0.93 ± 0.01, for MI-CB-DLM (without GA); 0.75 ± 0.03, 0.75 ± 0.03, 0.75 ± 0.03, 0.75 ± 0.03, 0.81 ± 0.03, for MI-VB-DLM (without GA); 0.81 ± 0.01, 0.81 ± 0.01, 0.81 ± 0.01, 0.81 ± 0.01, 0.89 ± 0.01, for MI-FE-DLM (without GA); and 0.86 ± 0.01, 0.86 ± 0.01, 0.86 ± 0.01, 0.86 ± 0.01, 0.93 ± 0.01, for MI-CB-DLM with GA. DATA CONCLUSION: MI-CB-DLM performed better than other DLMs. Including GA as an input of MI-CB-DLM improved its performance. MI-CB-DLM may potentially be used to objectively and rapidly assess fetal MR image quality. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 3.

Prenatal diagnosis of diencephalic-mesencephalic junction dysplasia: Fetal magnetic resonance imaging phenotypes, genetic diagnoses, and outcomes.

OBJECTIVE: Report a single-center 12-year experience in the fetal diagnosis of diencephalic-mesencephalic junction dysplasia (DMJD) to expand the phenotype with Magnetic resonance imaging (MRI)-based classification, evaluate genetic etiologies, and ascertain outcomes. METHODS: Retrospective medical record and imaging review of all fetal MRI exams with DMJD were performed at our institution. RESULTS: Thirty-three pregnancies with fetal MRI findings of DMJD at 24 (18-37) weeks gestational age were studied; 70% were referred for fetal hydrocephalus. Three fetal MRI patterns were recognized. Type A (butterfly/hypothalamus-midbrain union) was seen in two cases (6%), Type B (partial thalamus-midbrain union) in 22 fetuses (70%), and Type C (complete/near complete midbrain-thalamic continuity) in nine fetuses (24%). L1CAM mutations were identified in four cases, and biallelic VRK1 variants in another. Among 14 live-born cases, 11 survived infancy, and 10 underwent postnatal brain MRI which confirmed the fetal MRI diagnosis in all but one case. Development was delayed in all surviving infants, most with additional neurological sequelae. CONCLUSIONS: DMJD may be identified by prenatal MRI as early as 18 weeks gestation. We propose three distinct phenotypic forms of DMJD, Types A-C. Next-generation sequencing provides an underlying molecular diagnosis in some patients, but further studies on associated genetic diagnoses and clinical outcomes are indicated.

Cochlear signal alterations using pseudo-color perceptual enhancement for patients with sensorineural hearing loss.

BACKGROUND: Neuroimaging detection of sensorineural hearing loss (SNHL)-related temporal bone abnormalities is limited (20-50%). We hypothesize that cochlear signal differences in gray-scale data may exceed the threshold of human eye detection. Gray-scale images can be post-processed to enhance perception of tonal difference using "pseudo-color" schemes. OBJECTIVE: To compare patients with unilateral SNHL to age-matched normal magnetic resonance imaging (MRI) exams for "labyrinthine color differences" employing pseudo-color post-processing. MATERIALS AND METHODS: The MRI database at an academic children's hospital was queried for "hearing loss." Only unilateral SNHL cases were analyzed. Sixty-nine imaging exams were reviewed. Thirteen age-matched normal MR exams in children without hearing loss were chosen for comparison. Pseudo-color was applied with post-processing assignment of specific hues to each gray-scale intensity value. Gray-scale and pseudo-color images were qualitatively evaluated for signal asymmetries by a board-certified neuroradiologist blinded to the side of SNHL. RESULTS: Twenty-six SNHL (mean: 7.6±3 years) and 13 normal control exams (mean: 7.3±4 years) were included. All patients had normal gray-scale cochlear signal and all controls had symmetrical pseudo-color signal. However, pseudo-color images revealed occult asymmetries localizing to the SNHL ear with lower values in 38%. Ninety-one percent of these cases showed concordance between the side of pseudo-color positivity and the side of hearing loss. CONCLUSION: Pseudo-color perceptual image enhancement reveals intra-labyrinthine fluid alterations on MR exams in children with unilateral SNHL. Pseudo-color image enhancement techniques improve detection of cochlear pathology and could have therapeutic implications.

Taenia-tela choroidea complex and choroid plexus location help distinguish Dandy-Walker malformation and Blake pouch cysts.

BACKGROUND: Dandy-Walker malformation and Blake pouch cysts can have overlapping imaging features. The choroid plexus and associated taenia-tela choroidea complex are displaced inferolaterally in Dandy-Walker malformation and below the vermis in Blake pouch cysts. OBJECTIVE: To determine the normal fetal and postnatal MR appearance of the choroid plexus and taenia-tela choroidea complex, and whether their location can help distinguish Dandy-Walker malformation from Blake pouch cysts. MATERIALS AND METHODS: In this retrospective study, we evaluated brain MR exams from normal-appearing fetuses (gestational age 19-38 weeks) and infants, fetal and postnatal exams in Blake pouch cysts and Dandy-Walker malformation, and ambiguous cases equivocal for mild Dandy-Walker malformation and Blake pouch cysts. We documented choroid plexus and the taenia-tela choroidea complex location and axial and sagittal angles in each case. Then we contrasted and compared the original and updated fetal diagnoses based on taenia-tela choroidea complex and choroid plexus positions. RESULTS: The choroid plexus location and the taenia-tela choroidea complex location and angles varied significantly among normal exams, Blake pouch cyst exams and Dandy-Walker malformation exams (P<0.01). Dandy-Walker malformation showed inferolateral displacement of the taenia-tela choroidea complex and choroid plexus distant from the vermis. Adding the taenia-tela choroidea complex and choroid plexus into the assessment improved diagnostic accuracy, especially in ambiguous cases. CONCLUSION: The location of the taenia-tela choroidea complex and choroid plexus provided additional diagnostic neuroimaging clues that could be used in conjunction with other conventional findings to distinguish Dandy-Walker malformation and Blake pouch cysts. Normal, Blake pouch cyst, and Dandy-Walker malformation cases differed with regard to taenia-tela choroidea complex and choroid plexus position. Inferolateral taenia-tela choroidea complex displacement distant from the vermian margin was characteristic of Dandy-Walker malformation.

Risk Factors for Brain Injury in Newborns Treated with Extracorporeal Membrane Oxygenation.

OBJECTIVE: This study aimed to assess the association of clinical risk factors with severity of magnetic resonance imaging (MRI) brain injury in neonatal extracorporeal membrane oxygenation (ECMO) patients. STUDY DESIGN: This is a single-center retrospective study conducted at an outborn level IV neonatal intensive care unit in a free-standing academic children's hospital. Clinical and MRI data from neonates treated with ECMO between 2005 and 2015 were reviewed. MRI injury was graded by two radiologists according to a modified scoring system that assesses parenchymal injury, extra-axial hemorrhage, and cerebrospinal fluid spaces. MRI severity was classified as none (score = 0), mild/moderate (score = 1-13.5), and severe (score ≥ 14). The relationship between selected risk factors and MRI severity was assessed by Chi-square, analysis of variance, and Kruskal-Wallis tests where appropriate. Combinative predictive ability of significant risk factors was assessed by logistic regression analyses. RESULTS: MRI data were assessed in 81 neonates treated with ECMO. Veno-arterial (VA) patients had more severe injury compared with veno-venous patients. There was a trend toward less severe injury over time. After controlling for covariates, duration of ECMO remained significantly associated with brain injury, and the risk for severe injury was significantly increased in patients on ECMO beyond 210 hours. CONCLUSION: Risk for brain injury is increased with VA ECMO and with longer duration of ECMO. Improvements in care may be leading to decreasing incidence of brain injury in neonatal ECMO patients. KEY POINTS: · Veno-arterial ECMO is associated with more brain injury by MRI compared with veno-venous ECMO.. · Longer duration of ECMO is significantly associated with severe brain injury by MRI.. · Risk for neurologic injury may be decreasing over time with advances in neonatal ECMO..

The fetal falx cerebelli.

BACKGROUND: The falx cerebelli is a retrocerebellar dural reflection. The MR spectrum of the fetal falx cerebelli has not been described. OBJECTIVE: To determine the prevalence of falx cerebelli abnormalities in the context of posterior fossa malformations and compare them to age-matched normal fetal MRI exams. MATERIALS AND METHODS: We reviewed all consecutive fetal MRIs performed over 1 year at a children's hospital. We assessed the falx cerebelli in each examination for location, morphology, size and number. Exams were grouped into (1) normal or non-brain/head abnormalities or (2) abnormal brain or craniofacial structures. We used chi square, linear regression and logistic regression analyses; P<0.05 was considered significant. RESULTS: We included 424 examinations (223 controls, 201 malformations) from 378 patients (mean gestational age 27±6 weeks). In the control group, the mean falx size was 2.6±1.2 mm (anteroposterior) × 11.0±3.2 mm (craniocaudal), with 80% retrovermian centered; the falx was linear (23%), Y-shape (15%), V-shape (22%) or U-shape (21%); it was unusually multiplicated (17%) or absent (<2%). Falx cerebellar abnormalities were more common in abnormal exams (59%; 119/201) than in normal exams (19%; 43/223) (P<0.001). The falx was abnormal with Blake pouch cysts (9/9, 100%) and rhombencephalosynapsis (3/4, 75%), absent in all Chiari II (n=9) and most Dandy-Walker malformations (5/6, 83%), commonly multiplicated in mega cisterna magna (14/22, 64%), and deviated or absent in cases with arachnoid cysts (3/3, 100%) and adhesions (4/5, 80%). CONCLUSION: Structural alterations of the falx cerebelli are more prevalent in fetuses with brain and craniofacial abnormalities. Specific changes offer clues to posterior fossa diagnoses.

Cochlear-facial dehiscence in a pediatric patient.

Temporal bone dehiscence is an infrequent but clinically important phenomenon. Cochlear-facial dehiscence, the rarest type, has been described only in adults. We report cochlear-facial dehiscence in a child. Knowledge of this entity is imperative for radiologists searching for anatomical markers of inner ear pathology and for cochlear implant planning.

The effect of unilateral stroke on autonomic function in the term newborn.

BACKGROUND: The mature cerebral cortex has a topographically organized influence on reflex autonomic centers of the brainstem and diencephalon and sympathetic activation coming primarily from the right hemisphere and parasympathetic activation from the left. In the term newborn, the maturational status of this central autonomic system remains poorly understood. METHODS: Sixteen term newborns admitted to Children's National with unilateral middle cerebral artery (MCA) strokes (n = 8 left, n = 8 right) had archived continuous electrocardiograph (EKG) signals available. We compared stroke laterality and severity with indices of autonomic function, as measured by heart rate variability. We performed both time- and frequency-domain analyses on the R-R interval (RRi) over 24h of continuous EKG data at around 7 days of age. RESULTS: Right MCA stroke significantly increased sympathetic tone, while left MCA stroke increased parasympathetic tone. Regardless of laterality, stroke severity was associated inversely with sympathetic tone and positively with parasympathetic tone. Surprisingly, injury to either insular region had no significant autonomic effect. Phenobarbital blood levels were positively associated with sympathetic tone and inversely related to parasympathetic tone. CONCLUSION: Based on these findings, it is difficult to reconcile the functional topography of the central autonomic system in term newborns with that currently proposed for the normal mature brain. Further investigation is clearly needed.

"Laser and the Tuber": thermal dynamic and volumetric factors influencing seizure outcomes in pediatric subjects with tuberous sclerosis undergoing stereoencephalography-directed laser ablation of tubers.

PURPOSE: Tuberous sclerosis (TSC) is a well-known cause of medically refractory epilepsy (MRE). Stereoencephalography-directed magnetic resonance-guided laser interstitial thermal therapy (SEEG-directed MRgLITT) is an emerging minimally invasive technique that appears aptly suited for the surgical management of TSC. Our aims are to present our experiences with patients who had undergone SEEG-directed MRgLITT to identify and treat cortical tubers responsible for clinical seizures and to perform an in-depth analysis of volumetric and thermal dynamic factors that may be related to seizure outcomes. METHODS: We studied all pediatric patients with MRE due to TSC who underwent SEEG-directed MRgLITT, investigating seizure outcomes in relation to thermal dynamic and volumetric factors. RESULTS: Eight cortical tubers from three pediatric patients were analyzed. Two of three patients had Engel I outcomes at last follow-up (median 18 months). Average A/T (ablation volume/tuber volume) ratio for Engel I outcomes was 1.28 (variance, 0.16) and 0.84 (variance, < 0.01) for all other outcomes (P = 0.035). There was a moderate positive correlation when comparing ablation energy to ablation volume (R2 = 0.65) in cortical tuber tissue. When the calcified tuber is excluded, the correlation is stronger (R2 = 0.77). Thus, the calculated energy needed to ablate 1 cm3 of cortical tuber tissue is 1263.6 J (calcified tuber) or 1089.5 J (non-calcified tuber). CONCLUSIONS: SEEG-directed MRgLITT appears to be a safe and effective technique in the management of pediatric patients with MRE due to TSC. The A/T ratio may be a useful indicator in predicting seizure outcomes.

Prevalence of pituitary cysts in children using modern magnetic resonance imaging techniques.

BACKGROUND: Pituitary pars intermedia/Rathke cleft cysts or cyst-like structures are commonly encountered in children undergoing brain magnetic resonance imaging (MRI), especially when examinations include thin-section, high-resolution sequences. OBJECTIVE: To determine the prevalence of pituitary cystic lesions in children at our institution using modern MRI technique, to assess for associated endocrinopathy and to address the need for follow-up. MATERIALS AND METHODS: We retrospectively reviewed 232 consecutive 1.5- and 3-T brain MRIs in children ages 0-18 years (mean: 8.3±5.3 years). We evaluated 3-D volumetric T1 spoiled gradient echo (SPGR) and axial T2-weighted sequences. Pituitary glands were evaluated for the presence, size and signal characteristics of cysts. Cyst volumes were measured in three orthogonal planes. Endocrine abnormalities were documented from the medical record. RESULTS: Pituitary cysts were present in 57.7% of children (n=134), with a mean linear measurement of 3.6±1.17 mm (range: 0.4 to 12.3 mm). The overwhelming majority of cysts were hyopointense on T1-W images (n=121, 90%) and isointense on T2-W images relative to the adenohypophysis (n=106, 79%). T1 hyperintense and T2 hypointense signals were present in a minority, 6.7% and 8%, respectively. Most cysts were occult on post-contrast T1-W images (n=24, 77%). Endocrine abnormalities were present in 2/134 (1.5%) of children with cysts (these were unrelated to the pituitary gland) versus 1/98 (1%) children without cysts (P=0.7). CONCLUSION: More often than not, pituitary cysts/cyst-like structures can be found incidentally in children using modern MRI techniques. Follow-up is not typically required if there are no associated symptoms or excessive size.

Cerebral Diffusivity Changes in Fetuses with Chiari II Malformation.

OBJECTIVES: Chiari II malformation is a congenital abnormality characterized by a small posterior fossa with downward displacement of the hindbrain into the foramen magnum. Diffusion-weighted imaging (DWI) can be used to quantitatively characterize brain injury and physiological maturation. We aim to evaluate DWI parameters of the infra- and supratentorial brain in fetuses with Chiari II malformation. METHODS: MRI and US studies of 26 fetuses with Chiari II malformation and 15 controls were evaluated for the presence/severity of hydrocephalus, myelomeningocele level, and brain apparent diffusion coefficient (ADC) values. Cerebral flow impedance parameters (resistance and pulsatile indexes, resistance index [RI], and pulsatility index [PI] respectively) from concurrently preformed fetal US were also evaluated. RESULTS: Of the Chiari II group, 16 fetuses had hydrocephalus. There was increasing severity of lateral ventriculomegaly in the high compared to low spinal dysraphism subgroups. There were significant lower ADC values in the frontal (p = 0.01) and temporal lobes (p = 0.05) in Chiari II group compared with normal, regardless of the presence or severity of hydrocephalus. Fetuses with Chiari II showed significantly lower RI and PI values. CONCLUSIONS: Abnormal ADC values indicate supratentorial microstructural changes in fetuses with Chiari II malformation. Further investigation of the role of diffusion imaging metrics in evaluating abnormal brain development, parenchymal damage and efficacy of fetal surgery is needed.