Publications by authors named "Liat Ben-Sira"

117 Publications

Utility of three-dimensional modeling of the fetal airway for ex utero intrapartum treatment.

J Anesth 2021 Jun 1. Epub 2021 Jun 1.

Division of Anesthesiology, Intensive Care, and Pain Medicine, Tel-Aviv Medical Center, affiliated with the Sackler Faculty of Medicine, 6 Weizmann Street, 6423906, Tel-Aviv, Israel.

Recent technological developments in three-dimensional (3D) printing have created new opportunities for applications in clinical medicine. 3D printing has been adopted for teaching and planning complicated surgeries, including maxillofacial, orthopedic reconstructions, and airway manipulation for one-lung ventilation or airway stenting. We present here the first use of such technology to print a model from in utero imaging for intrapartum treatment planning. A 32-week fetus presented with congenital high airway obstruction syndrome (CHAOS) due to a large cervical lymphatic malformation. An ex utero intrapartum treatment (EXIT) procedure was planned to allow delivery of a viable infant. We printed a 3D model of the fetal airway by printing separate elements: mandible, tongue, mass, larynx, and trachea from the fetal MRI. The elements were stuck together maintaining correct anatomical relationships. Airway planning was then performed in consultation with a pediatric ear nose and throat (ENT) surgeon. 3D modeling in utero presents many challenges: the resolution of the 3D model generated from a fetal MRI is less crisp than from CT images, fetal position may be variable and not in a defined anatomical plane, movement artifact occurs. Nevertheless, pre-procedure simulations with the aid of 3D modeling promoted team cooperation and well-prepared management of the fetus during EXIT.
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http://dx.doi.org/10.1007/s00540-021-02950-8DOI Listing
June 2021

Fetal and Perinatal Outcome Following First and Second Trimester COVID-19 Infection: Evidence from a Prospective Cohort Study.

J Clin Med 2021 May 16;10(10). Epub 2021 May 16.

Fetal Medicine Unit, Department of Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer 5262000, Israel.

A novel coronavirus termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new strain of coronavirus causing coronavirus disease 2019 (COVID-19) disease, which emerged as a global pandemic. Data regarding the implications of COVID-19 disease at early gestation on fetal and obstetric outcomes is scarce. Thus, our aim was to investigate the effect of first and second trimester maternal COVID-19 disease on fetal and perinatal outcomes. This was a prospective cohort study of pregnant women with a laboratory-proven SARS-COV-2 infection contracted prior to 26 weeks gestation. Women were followed at a single tertiary medical center by serial sonographic examinations every 4-6 weeks to assess fetal well-being, growth, placental function, anatomic evaluation and signs of fetal infection. Amniocentesis was offered to assess amniotic fluid SARS-COV-2-PCR (polymerase chain reaction) and fetal brain magnetic resonance imaging (MRI) was offered at 30-32 weeks gestation. Demographic, obstetric and neonatal data were collected from history intake, medical charts or by telephone survey. Perinatal outcomes were compared between women infected at first vs. second trimester. 55 women with documented COVID-19 disease at early gestation were included and followed at our center. The mean maternal age was 29.6 ± 6.2 years and the mean gestational age at viral infection was 14.2 ± 6.7 weeks with 28 (51%) women infected at the first trimester and 27 (49%) at the second trimester. All patients but one experienced asymptomatic to mild symptoms. Of 22 patients who underwent amniocentesis, none had evidence of vertical transmission. None of the fetuses exhibited signs of central nervous system (CNS) disease, growth restriction and placental dysfunction on serial ultrasound examinations and fetal MRI. Pregnancies resulted in perinatal survival of 100% to date with mean gestational age at delivery of 38.6 ± 3.0 weeks and preterm birth <37 weeks rate of 3.4%. The mean birthweight was 3260 ± 411 g with no cases of small for gestational age infants. The obstetric and neonatal outcomes were similar among first vs. second trimester infection groups. We conclude SARS-CoV-2 infection at early gestation was not associated with vertical transmission and resulted in favorable obstetric and neonatal outcomes.
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http://dx.doi.org/10.3390/jcm10102152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156528PMC
May 2021

White matter abnormalities and iron deposition in prenatal mucolipidosis IV- fetal imaging and pathology.

Metab Brain Dis 2021 May 8. Epub 2021 May 8.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Mucolipidosis type IV (MLIV; OMIM 252,650) is an autosomal recessive lysosomal disorder caused by mutations in MCOLN1. MLIV causes psychomotor impairment and progressive vision loss. The major hallmarks of postnatal brain MRI are hypomyelination and thin corpus callosum. Human brain pathology data is scarce and demonstrates storage of various inclusion bodies in all neuronal cell types. The current study describes novel fetal brain MRI and neuropathology findings in a fetus with MLIV. Fetal MRI was performed at 32 and 35 weeks of gestation due to an older sibling with spastic quadriparesis, visual impairment and hypomyelination. Following abnormal fetal MRI results, the parents requested termination of pregnancy according to Israeli regulations. Fetal autopsy was performed after approval of the high committee for pregnancy termination. A genetic diagnosis of MLIV was established in the fetus and sibling. Sequential fetal brain MRI showed progressive curvilinear hypointensities on T2-weighted images in the frontal deep white matter and a thin corpus callosum. Fetal brain pathology exhibited a thin corpus callosum and hypercellular white matter composed of reactive astrocytes and microglia, multifocal white matter abnormalities with mineralized deposits, and numerous aggregates of microglia with focal intracellular iron accumulation most prominent in the frontal lobes. This is the first description in the literature of brain MRI and neuropathology in a fetus with MLIV. The findings demonstrate prenatal white matter involvement with significant activation of microglia and astrocytes and impaired iron metabolism.
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http://dx.doi.org/10.1007/s11011-021-00742-3DOI Listing
May 2021

Deletion in COL4A2 is associated with a three-generation variable phenotype: from fetal to adult manifestations.

Eur J Hum Genet 2021 Apr 9. Epub 2021 Apr 9.

Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Genetic alterations in COL4A2 are less common than those of COL4A1 and their fetal phenotype has not been described to date. We describe a three-generation family with an intragenic deletion in COL4A2 associated with a prenatal diagnosis of recurrent fetal intracerebral hemorrhage (ICH), and a myriad of cerebrovascular manifestations. Exome sequencing, co-segregation analysis, and imaging studies were conducted on eight family members including two fetuses with antenatal ICH. Histopathological evaluation was performed on the terminated fetuses. An intragenic heterozygous pathogenic in-frame deletion; COL4A2, c.4151_4168del, (p.Thr1384_Gly1389del) was identified in both fetuses, their father with hemiplegic cerebral palsy (CP), as well as other family members. Postmortem histopathological examination identified microscopic foci of heterotopias and polymicrogyria. The variant segregated in affected individuals demonstrating varying degrees of penetrance and a wide phenotypic spectrum including periventricular venous hemorrhagic infarction causing hemiplegic CP, polymicrogyria, leukoencephalopathy, and lacunar stroke. We present radiographic, pathological, and genetic evidence of prenatal ICH and show, for what we believe to be the first time, a human pathological proof of polymicrogyria and heterotopias in association with a COL4A2 disease-causing variant, while illustrating the variable phenotype and partial penetrance of this disease. We highlight the importance of genetic analysis in fetal ICH and hemiplegic CP.
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http://dx.doi.org/10.1038/s41431-021-00880-3DOI Listing
April 2021

MRI-based diagnosis and treatment of pediatric brain tumors: is tissue sample always needed?

Childs Nerv Syst 2021 May 5;37(5):1449-1459. Epub 2021 Apr 5.

Departments of Neurosurgery and Pediatric Neurosurgery, Tel-Aviv Medical Center and Dana Children's Hospital, Tel Aviv University, 6 Weizmann Street, Tel Aviv, Israel.

Traditional management of newly diagnosed pediatric brain tumors (PBTs) consists of cranial imaging, typically magnetic resonance imaging (MRI), and is frequently followed by tissue diagnosis, through either surgical biopsy or tumor resection. Therapy regimes are typically dependent on histological diagnosis. To date, many treatment regimens are based on molecular biology. The scope of this article is to discuss the role of diagnosis and further treatment of PBTs based solely on MRI features, in light of the latest treatment protocols. Typical MRI findings and indications for surgical biopsy of these lesions are described.
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http://dx.doi.org/10.1007/s00381-021-05148-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084800PMC
May 2021

Delineation of the phenotype of MED17-related disease in Caucasus-Jewish families.

Eur J Paediatr Neurol 2021 May 5;32:40-45. Epub 2021 Mar 5.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Ramat Gan, Israel.

Background: and Purpose: Postnatal progressive microcephaly, with seizures and brain atrophy (OMIM # 613668) is a rare disorder caused by a homozygous founder missense mutation c.1112T>C (p.L371P) in the MED17 gene on chromosome 11 that was identified in 2010 in Caucasus Jewish families. The present study aimed to delineate the phenotype and developmental outcomes in patients diagnosed with this mutation to date.

Methods: We conducted a medical charts review to collect the clinical, laboratory and neuroimaging findings in patients from several unrelated families of Caucasus-Jewish origin, who were diagnosed with the same homozygous c.1112T>C MED17 mutation.

Results: The study cohort, including the previously reported patients, comprised 10 males and 5 females from 11 families. All subjects had at birth a normal head circumference, which steeply declined to -6SD within a few months. None of the patients achieved developmental milestones. All patients had progressive spasticity and were wheelchair bound due to spastic quadriplegia. All of them eventually developed profound intellectual disability. Epilepsy of varied severity was present in all patients. Most patients required enteral feeding due to aspirations. Eight patients died before puberty (age range 2-13 years). Brain MRI showed marked cerebral atrophy and early prominent cerebellar atrophy (vermian > hemispheres) accompanied by pontine ventral flattening.

Conclusions: The founder c.1112T>C mutation in MED17 gene is expressed by a unique and homogeneous clinical phenotype with distinctive MRI findings. This mutation should be considered in patients of Caucasus-Jewish ancestry presenting with clinical features and a MRI pattern of progressive cerebral and cerebellar atrophy.
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http://dx.doi.org/10.1016/j.ejpn.2020.08.011DOI Listing
May 2021

The Role of 3D Reconstruction of the Skull in Patients with Suspected Shunt Malfunction.

Pediatr Neurosurg 2021 17;56(2):110-115. Epub 2021 Mar 17.

Departments of Neurosurgery and Pediatric Neurosurgery, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel.

Background: Mechanical shunt malfunction may lead to significant morbidity and mortality. Shunt series assessments help evaluate shunt integrity; however, they are of limited value in the area of the skull due to skull curvature, thickness, and air sinuses. We describe the role of 3D bone reconstruction CT (3DCT) in demonstrating the shunt integrity over the skull, comparing this technique to skull X-rays (SXR).

Methods: Data were collected retrospectively for shunted patients with concurrent SXR and 3DCT and for patients presenting with shunt failures at the region of the skull, including clinical course and radiological findings. We compared the SXR and 3DCT findings. The 3DCT was reconstructed from standard diagnostic CT protocols performed during evaluation of suspected shunt malfunction and not thin-slice CT protocols.

Results: Forty-eight patients with 57 shunts underwent SXR and 3DCT. Interobserver agreement was high for most variables. Both SXR and 3DCT had a high sensitivity, specificity, and accuracy identifying tubing disconnections (between 0.83 and 1). Full valve type and setting were significantly more accurate based on SXR versus 3DCT (>90 vs. <20%), and valve integrity was significantly more readily verified on 3DCT versus SXR (100 vs. 52%).

Conclusions: 3DCT and SXR complement each other in diagnosing mechanical shunt malfunctions over the skull. The main limitation of 3DCT is identification of valve type and settings, which are clearer on SXR, while the main limitation of SXR is a less ability to evaluate valve integrity. 3DCT also enables an intuitive 3D understanding of the shunt tubing over the skull.
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http://dx.doi.org/10.1159/000514065DOI Listing
March 2021

Sarcopenia is a Predictor for Adverse Clinical Outcome in Pediatric Inflammatory Bowel Disease.

J Pediatr Gastroenterol Nutr 2021 Jun;72(6):883-888

Pediatric Gastroenterology Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Objectives: Inflammatory bowel disease (IBD) has a high impact on nutritional status. Sarcopenia is related to higher risk of surgery and rescue therapy in adults with IBD; however, comparable data in pediatric populations are scarce. We evaluated muscle mass as a predictor of disease outcome in pediatric IBD.

Methods: All pediatric IBD patients who underwent magnetic resonance enterography (MRE) during 2008 to 2019 were included. Muscle mass was assessed by measuring the area of the psoas muscle at the upper level of L3 on MRE. The psoas area divided by the body surface area (BSA) yielded the psoas index. Clinical and radiological data, including disease location, activity, course, and medications were documented. The control group included non-IBD children who underwent an MR imaging study.

Results: We enrolled 101 IBD patients, 69 (68.3%) with Crohn disease (CD) and 32 (31.7%) with ulcerative colitis (UC) (mean age 15.03 ± 3.27 years). The psoas index was significantly lower in the IBD patients compared with the 87 controls (326 vs 528, respectively, P < 0.001). Patients with a psoas index in the lowest quartile had significantly higher risk for biologic therapy (multivariate analysis, hazard ratio [HR] = 12.1, P = 0.046) and disease exacerbation (HR = 9, P = 0.047) independently of body mass index, compared with patients with a psoas index in the uppermost quartile.

Conclusions: Sarcopenia correlates with the radiological severity of pediatric IBD and serves as a predictor for adverse clinical disease outcome. Muscle mass measurement in MRE studies may serve as a possible marker for disease outcome in this population.
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http://dx.doi.org/10.1097/MPG.0000000000003091DOI Listing
June 2021

Monogenic Causes of Apparently Idiopathic Perinatal Intracranial Hemorrhage.

Ann Neurol 2021 04 16;89(4):813-822. Epub 2021 Feb 16.

Sackler Faulty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Objective: Perinatal intracranial hemorrhage (pICH) is a rare event that occurs during the fetal/neonatal period with potentially devastating neurological outcome. However, the etiology of pICH is frequently hard to depict. We investigated the role of rare genetic variations in unexplained cases of pICH.

Methods: We performed whole-exome sequencing (WES) in fetuses and term neonates with otherwise unexplained pICH and their parents. Variant causality was determined according to the American College of Medical Genetics and Genomics (ACMG) criteria, consistency between suggested genes and phenotypes, and mode of inheritance.

Results: Twenty-six probands (25 families) were included in the study (9 with a prenatal diagnosis and 17 with a postnatal diagnosis). Intraventricular hemorrhage (IVH) was the most common type of hemorrhage (n = 16, 62%), followed by subpial (n = 4, 15%), subdural (n = 4, 15%), and parenchymal (n = 2, 8%) hemorrhage. Causative/likely causative variants were found in 4 subjects from 3 of the 25 families (12%) involving genes related to the brain microenvironment (COL4A1, COL4A2, and TREX-1). Additionally, potentially causative variants were detected in genes related to coagulation (GP1BA, F11, Von Willebrand factor [VWF], FGA, and F7; n = 4, 16%). A potential candidate gene for phenotypic expansion related to microtubular function (DNAH5) was identified in 1 case (4%). Fifty-five percent of the variants were inherited from an asymptomatic parent. Overall, these findings showed a monogenic cause for pICH in 12% to 32% of the families.

Interpretation: Our findings reveal a clinically significant diagnostic yield of WES in apparently idiopathic pICH and support the use of WES in the evaluation of these cases. ANN NEUROL 2021;89:813-822.
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http://dx.doi.org/10.1002/ana.26033DOI Listing
April 2021

Incidental Findings on Brain Magnetic Resonance Imaging (MRI) in Pediatric Endocrine Patients.

Endocr Pract 2020 Oct;26(10):1105-1114

From the Pediatric Endocrinology and Diabetes Unit, Tel-Aviv, Israel.

Objective: To explore incidental findings on brain magnetic resonance imaging (MRI) studies of pediatric patients referred due to endocrine disorders.

Methods: A retrospective, observational study conducted in a tertiary referral center. The neuroimaging database of 17,445 brain MRI studies of 11,011 pediatric patients were searched for cases with endocrine referrals and without medical history of malignancy, genetic syndromes, and/or neurologic comorbidities. This database was linked to the pediatric neurosurgical database. Clinical data were retrieved from medical files.

Results: In total, 524 patients (50.2% males, mean age 8.5±3.5 years) were referred to brain MRI due to growth disturbances (n = 313), pubertal disorders (n = 183), prolactin hypersecretion (n = 18), central diabetes insipidus (n = 8), and obesity (n = 1). Incidental findings were found in 128 (24.4%) cases. Chiari type 1 malformation was more prevalent in patients with growth disturbances (P<.001). Small pituitary cysts were observed in 20 (3.8%) patients, and pineal cysts in 25 (4.8%) patients, mostly girls (68%, P<.001). White matter lesions were diagnosed in 30 (5.7%) patients, none with clinical evidence of neurologic disease. Brain asymmetry without clinical significance and developmental venous anomalies were observed in 14 (2.7%) and 8 (1.5%) patients, respectively. Twelve patients were diagnosed with intracranial tumors, and 5 required surgical intervention for a histopathologic diagnosis of juvenile pilocytic astrocytoma (n = 3), choroid plexus papilloma (n = 1), or inconclusive (n = 1). The rest were managed conservatively.

Conclusion: Incidental findings on brain MRIs of pediatric patients referred by endocrinologists are common and raise dilemmas. The spectrum ranges from structural disruptions to tumors. Decision-making is individualized and patient-centered.
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http://dx.doi.org/10.4158/EP-2020-0208DOI Listing
October 2020

A unique brain germinal matrix involvement in cytomegalovirus infected fetuses: A retrospective neurosonographic analysis with outcome correlation.

Prenat Diagn 2021 Jan 13. Epub 2021 Jan 13.

OB-GYN Ultrasound Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Objective: To study the clinical significance of brain germinal matrix (GM) changes in cytomegalovirus (CMV) infected fetuses.

Method: This is a retrospective analysis. Group A; isolated GM finding, with or without lenticulostriatal vasculopathy (LSV). Group B; non-isolated lesion. Amniocentesis, urinalysis, postnatal US and developmental assessment, were obtained.

Results: Group A and B included 18 and four fetuses, respectively. In group A, mean fetal age at diagnosis was 34.3 weeks (31-38 weeks). In 15/18 (83.3%), the lesion was bilateral and LSV was present in 8/18 (44.4%). Small cysts appeared inside the lesion in 5/18 (27.7%). MRI was normal in 8/18 (44.4%). Subtle or inconclusive findings were reported in the remaining fetuses. Brain ultrasound was normal in 10/18 (55.5%) of newborns. In the remaining, caudothalamic cyst with or without LSV, or isolated LSV were found. All newborns are developing normally at a mean follow-up age of 33.3 months (+/- 19.6 moths). In group B, all four patients requested for termination of pregnancy.

Conclusion: Fetal CMV infection may cause focal GM changes, frequently accompanied by LSV, late in pregnancy. These changes may be isolated, or as part of a more generalized brain damage. When isolated, favorable prognosis is expected.
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http://dx.doi.org/10.1002/pd.5888DOI Listing
January 2021

Neurodevelopmental outcome of children born with an isolated atretic cephalocele.

Childs Nerv Syst 2021 Apr 6;37(4):1295-1300. Epub 2021 Jan 6.

Pediatric Neurology Institute, The Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, 6423906, Tel Aviv, Israel.

Purpose: The existing data on the neurodevelopmental outcome of children born with an isolated atretic cephalocele (IAC) are scant. We aimed to expand upon these data by describing our experience with affected children, as well as assist parents and clinicians in deciding how to proceed when an IAC is diagnosed prenatally.

Methods: A follow-up study was conducted on nine children who were born with an IAC. Evaluations were performed by pediatric neurologists and child development specialists. Developmental outcomes were based on a global development evaluation that assessed gross and fine motor skills, receptive and expressive language levels, activities of daily living, communication skills, and social domains. Adaptive skills were estimated by the Adaptive Behavior Assessment System, Second Edition.

Results: None of the nine children (median age 4 years and 6 months) had abnormal findings on neurological examination. Six children had age-appropriate developmental milestones, two had a mild motor delay, and one had mild expressive language delay (catchup was achieved by all of the latter three by ~ 3.5 years of age). The mean general adaptive composite score was 105 ± 11.7 (normal = 100). None of the children had behavioral, social, or communication problems.

Conclusions: Children diagnosed with an IAC with/without a falcine sinus and devoid of coexisting intracranial abnormalities seem to have a normal neurodevelopmental outcome. Continuation of pregnancy may be recommended when an IAC is detected prenatally, and reassurance if detected postnatally.
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http://dx.doi.org/10.1007/s00381-020-04997-6DOI Listing
April 2021

Automatic segmentation, classification, and follow-up of optic pathway gliomas using deep learning and fuzzy c-means clustering based on MRI.

Med Phys 2020 Nov 8;47(11):5693-5701. Epub 2020 Oct 8.

Sagol Brain Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, 6423906, Israel.

Purpose: Optic pathway gliomas (OPG) are low-grade pilocytic astrocytomas accounting for 3-5% of pediatric intracranial tumors. Accurate and quantitative follow-up of OPG using magnetic resonance imaging (MRI) is crucial for therapeutic decision making, yet is challenging due to the complex shape and heterogeneous tissue pattern which characterizes these tumors. The aim of this study was to implement automatic methods for segmentation and classification of OPG and its components, based on MRI.

Methods: A total of 202 MRI scans from 29 patients with chiasmatic OPG scanned longitudinally were retrospectively collected and included in this study. Data included T and post-contrast T weighted images. The entire tumor volume and its components were manually annotated by a senior neuro-radiologist, and inter- and intra-rater variability of the entire tumor volume was assessed in a subset of scans. Automatic tumor segmentation was performed using deep-learning method with U-Net+ResNet architecture. A fivefold cross-validation scheme was used to evaluate the automatic results relative to manual segmentation. Voxel-based classification of the tumor into enhanced, non-enhanced, and cystic components was performed using fuzzy c-means clustering.

Results: The results of the automatic tumor segmentation were: mean dice score = 0.736 ± 0.025, precision = 0.918 ± 0.014, and recall = 0.635 ± 0.039 for the validation data, and dice score = 0.761 ± 0.011, precision = 0.794 ± 0.028, and recall = 0.742 ± 0.012 for the test data. The accuracy of the voxel-based classification of tumor components was 0.94, with precision = 0.89, 0.97, and 0.85, and recall = 1.00, 0.79, and 0.94 for the non-enhanced, enhanced, and cystic components, respectively.

Conclusion: This study presents methods for automatic segmentation of chiasmatic OPG tumors and classification into the different components of the tumor, based on conventional MRI. Automatic quantitative longitudinal assessment of these tumors may improve radiological monitoring, facilitate early detection of disease progression and optimize therapy management.
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http://dx.doi.org/10.1002/mp.14489DOI Listing
November 2020

Short and thick corpus callosum - the thin border between a minor anatomical variant to very poor outcome.

J Matern Fetal Neonatal Med 2020 Sep 22:1-4. Epub 2020 Sep 22.

Obstetrics and Gynecology Ultrasound Unit, Rabin Medical Center, Helen Schneider Hospital for Women, Petach Tikva, Israel.

The corpus callosum (CC) is the largest commissure connecting the cerebral hemispheres. Its components are recognized sonographically at 18-20 GW and from that point forward, its growth can be assessed using nomograms for CC length and thickness according to gestational week. Prenatal diagnosis of agenesis of the CC has been reported comprehensively. On the contrary, information regarding findings as short or thick CC is very rare. Is short CC an expression of callosal dysgenesis or could it be a variant of the normal development when all its parts exist? We discuss this issue through this case report.
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http://dx.doi.org/10.1080/14767058.2020.1818208DOI Listing
September 2020

Placental vascular tree characterization based on ex-vivo MRI with a potential application for placental insufficiency assessment.

Placenta 2020 11 31;101:252-260. Epub 2020 Aug 31.

Sagol Brain Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. Electronic address:

Introduction: Understanding regarding the whole placental vascular network structure is limited. Our aim was to quantitatively characterize the human placental vascular tree ex-vivo using high-resolution MRI.

Methods: 34 normal placentas were rinsed and injected with a solution of gelatin and contrast agent through the umbilical vessels. A sample of six placentas taken from pregnancies with intrauterine-growth-restriction (IUGR) was used to demonstrate the potential application to cases with placental insufficiency. Structural ex-vivo MR scans of the placenta were performed using high resolution T weighted images. A semi-automatic method was developed to segment and characterize the placental vascular architecture: placental volume and cord insertion location; number of bifurcations, generations and vessels diameters.

Results: Different vascular patterns were found in placentas with central versus marginal cord-insertion. Based on the placental volume and number of bifurcations we were able to predict birth weight. Furthermore, preliminary results on IUGR sample demonstrated the potential of this method to differentiate between small newborns with suspected IUGR from small normal newborns who reached their full growth potential. Results obtained using the automatic method were validated against manual values demonstrating no significant differences or bias. Histopathology supported the imaging findings.

Discussion: This is the first study to quantitatively characterize the human placental vascular architecture using high resolution ex-vivo MRI. Different patterns of vascular architecture may be related to different functioning of the placenta and affect fetal development. This method is simple, relatively fast, provides detailed information of the placental vascular architecture, and may have important clinical applications.
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http://dx.doi.org/10.1016/j.placenta.2020.08.001DOI Listing
November 2020

INCIDENTAL FINDINGS ON BRAIN MAGNETIC RESONANCE IMAGING (MRI) IN PEDIATRIC ENDOCRINE PATIENTS.

Endocr Pract 2020 Jun 23. Epub 2020 Jun 23.

From: Pediatric Endocrinology and Diabetes Unit.

To explore incidental findings on brain magnetic resonance imaging (MRI) studies of pediatric patients referred due to endocrine disorders. A retrospective, observational study conducted in a tertiary referral center. The neuroimaging database of 17,445 brain MRI studies of 11,011 pediatric patients were searched for cases with endocrine referrals and without medical history of malignancy, genetic syndromes and/or neurological comorbidities. This database was linked to the pediatric neurosurgical database. Clinical data were retrieved from medical files. In total, 524 patients (50.2% males, mean age 8.5±3.5 years) were referred to brain MRI due to growth disturbances (n=313), pubertal disorders (n=183), prolactin hypersecretion (n=18), central diabetes insipidus (n=8) and obesity (n=1). Incidental findings were found in 128 (24.4%) cases. Chiari type 1 malformation was more prevalent in patients with growth disturbances (<.001). Small pituitary cysts were observed in 20 (3.8%) patients, and pineal cysts in 25 (4.8%) patients, mostly girls (68%, <.001). White matter lesions were diagnosed in 30 (5.7%) patients, none with clinical evidence of neurologic disease. Brain asymmetry without clinical significance and developmental venous anomalies were observed in 14 (2.7%) and 8 (1.5%) patients, respectively. Twelve patients were diagnosed with intracranial tumors, and 5 required surgical intervention for a histopathological diagnosis of juvenile pilocytic astrocytoma (n=3), choroid plexus papilloma (n=1), or inconclusive (n=1). The rest were managed conservatively. Incidental findings on brain MRIs of pediatric patients referred by endocrinologists are common and raise dilemmas. The spectrum ranges from structural disruptions to tumors. Decision-making is individualized and patient-centered.
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http://dx.doi.org/10.4158/EP-2020-0208DOI Listing
June 2020

Placental vascular tree characterization based on ex-vivo MRI with a potential application for placental insufficiency assessment.

Placenta 2020 07 19;96:34-43. Epub 2020 May 19.

Sagol Brain Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. Electronic address:

Introduction: Understanding regarding the whole placental vascular network structure is limited. Our aim was to quantitatively characterize the human placental vascular tree ex-vivo using high-resolution MRI.

Methods: 34 normal placentas were rinsed and injected with a solution of gelatin and contrast agent through the umbilical vessels. A sample of six placentas taken from pregnancies with intrauterine-growth-restriction (IUGR) was used to demonstrate the potential application to cases with placental insufficiency. Structural ex-vivo MR scans of the placenta were performed using high resolution T weighted images. A semi-automatic method was developed to segment and characterize the placental vascular architecture: placental volume and cord insertion location, number of bifurcations, generations and vessels diameters.

Results: Different vascular patterns were found in placentas with central versus marginal cord-insertion. Based on the placental volume and number of bifurcations we were able to predict birth weight. Furthermore, preliminary results on IUGR sample demonstrated the potential of this method to differentiate between small newborns with suspected IUGR from small normal newborns who reached their full growth potential. Results obtained using the automatic method were validated against manual values demonstrating no significant differences or bias. Histopathology supported the imaging findings.

Discussion: This is the first study to quantitatively characterize the human placental vascular architecture using high resolution ex-vivo MRI. Different patterns of vascular architecture may be related to different functioning of the placenta and affect fetal development. This method is simple, relatively fast, provides detailed information of the placental vascular architecture, and may have important clinical applications.
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http://dx.doi.org/10.1016/j.placenta.2020.05.001DOI Listing
July 2020

Neurofibromatosis 1-associated optic pathway gliomas.

Childs Nerv Syst 2020 10 11;36(10):2351-2361. Epub 2020 Jun 11.

Department of Pediatric Neurosurgery, Dana Children's Hospital, Tel-Aviv Medical Center, The Gilbert Israeli International Neurofibromatosis Center (GIINFC), Tel Aviv University, 6th Weizmann St., 64239, Tel-Aviv, Israel.

Background: Optic Pathway Gliomas (OPG) are the most common brain tumor in Neurofibromatosis 1 patients (NF1). They are found along the optic pathway and may involve the optic nerves, chiasm, retro-chiasmatic structures, and the optic radiations. NF1 associate OPG (NF1-OPG) have variable presentation, disease course and response to treatment. The optimal management is patient-specific and should be tailored by a multidisciplinary team. Age, sex, histology, and molecular markers may be important factors in the individualized decision-making process. Chemotherapy is the first-line treatment in cases of progressive tumors, and visual preservation is the main goal of treatment.

Purpose: In this paper we will review the disease, practical management, and recent advances of NF1-OPG.
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http://dx.doi.org/10.1007/s00381-020-04697-1DOI Listing
October 2020

The Clinical Utility of Inpatient Brain Magnetic Resonance Imaging in Children.

J Child Neurol 2020 10 10;35(11):744-752. Epub 2020 Jun 10.

Sackler School of Medicine, 26745Tel-Aviv University, Israel.

The clinical applicability and yield of brain magnetic resonance imaging (MRI) in the setting of an inpatient pediatric department has not been investigated. The authors performed a retrospective chart review of nontraumatic/nonneurosurgical children who underwent brain MRI during their hospitalization in a general pediatric department over a 5-year period. Of the 331 children who underwent brain MRI, 148 (45%) had abnormal findings. High-risk headaches and focal seizures were significantly correlated with findings on brain MRI. Diagnostic and therapeutic yields were most significant in acute demyelinating events, acute cerebrovascular disorders, high-risk headaches when supported by neurologic and ophthalmologic findings, focal seizures with evidence of multifocal epileptic activity on an electroencephalogram and ophthalmic complaints when accompanied by cranial nerve palsy and optic nerve impairment. Since the contributions of a brain MRI in hospitalized children is pivotal in specific clinical situations, a judicious decision-making process should be done before its scheduling, in order to optimize clinical care.
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http://dx.doi.org/10.1177/0883073820931264DOI Listing
October 2020

Expanding the genotype-phenotype spectrum of ISCA2-related multiple mitochondrial dysfunction syndrome-cavitating leukoencephalopathy and prolonged survival.

Neurogenetics 2020 10 18;21(4):243-249. Epub 2020 May 18.

Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel.

Iron-sulfur cluster assembly 2 (ISCA2)-related multiple mitochondrial dysfunction syndrome 4 (MMDS4) is a fatal autosomal recessive mitochondrial leukoencephalopathy. The disease typically manifests with rapid neurodevelopmental deterioration during the first months of life leading to a vegetative state and early death. MRI demonstrates a demyelinating leukodystrophy. We describe an eleven-year-old boy with a milder phenotype of ISCA2 related disorder manifesting as: normal early development, acute infantile neurologic deterioration leading to stable spastic quadriparesis, optic atrophy and mild cognitive impairment. The first MRI demonstrated a diffuse demyelinating leukodystrophy. A sequential MRI revealed white matter rarefaction with well-delineated cysts. The patient harbors two novel bi-allelic variants (p.Ala2Asp and p.Pro138Arg) in ISCA2 inherited from heterozygous carrier parents. This report expands the clinical spectrum of ISCA2-related disorders to include a milder phenotype with a longer life span and better psychomotor function and cavitating leukodystrophy on MRI. We discuss the possible genetic explanation for the different presentation.
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http://dx.doi.org/10.1007/s10048-020-00611-8DOI Listing
October 2020

Management of incidental brain tumors in children: a systematic review.

Childs Nerv Syst 2020 08 6;36(8):1607-1619. Epub 2020 May 6.

Department of Pediatric Neurosurgery, Tel Aviv Medical Center & Dana Children's Hospital Tel Aviv, Weizman Street 12, Tel Aviv, Israel.

Background: Due to technical advancements and availability of neuroimaging, detection of incidental pediatric brain tumors (IPBT) is growing rapidly. The management of these asymptomatic lesions remains unclear; radiological, pathological, and clinical risk factors for further growth and malignant transformation (MT) are not well defined.

Methods: We systematically reviewed the literature on the dilemmas and management of IPBT suggestive of a low-grade brain tumor (LGBT). Keyword searches of the PubMed and Medline (NCBI) databases identified studies on IPBT describing the prevalence, neuroimaging, management, or risk of MT through July 2019. References of the identified articles were also reviewed.

Results: A total of 2021 records were screened. Fifty-nine full-text articles were reviewed, and 34 published studies were included. IPBT are diagnosed in 0.2-5.7% of children undergoing brain imaging for various reasons. The accepted approach for management of lesions showing radiological characteristics suggestive of LGBT is radiological follow-up. The rate at which additional intervention is required during follow-up for these apparently low-grade lesions is 9.5%. Nevertheless, the dilemma of early surgical resection or biopsy vs. clinical and radiological follow-up of IPBT is still unresolved. The risk in these cases is missing a transformation to a higher grade tumor. However, MT of pediatric LGBT is very rare, occurring in less than 3% of the cases of proven low-grade gliomas in children. The risk of future MT in pediatric low-grade gliomas seems to be greater in the presence of specific molecular markers such as BRAF V-600E, CDKN2A, and H3F3A K27M.

Conclusions: The natural history, management, and prognosis of IPBT remain ambiguous. It seems that lesions suggestive of LGBT can initially be followed, since many of these lesions remain stable over time and MT is rare. However, controversy among centers concerning the ideal approach still exists. Further observational and prospective cohort studies, focusing on potential clinical and radiological characteristics or risk factors suggestive of high-grade tumors, tumor progress, or MT of IPBT, are needed.
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http://dx.doi.org/10.1007/s00381-020-04658-8DOI Listing
August 2020

Autosomal dominant TUBB3-related syndrome: Fetal, radiologic, clinical and morphological features.

Eur J Paediatr Neurol 2020 May 4;26:46-60. Epub 2020 Mar 4.

Metabolic Neurogenetic Service, Wolfson Medical Center, Holon, Israel; Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Objective: To describe fetal, clinical, radiological, morphological features of TUBB3 related syndrome.

Methods: We report two families each of two generations harboring a novel and a previously described heterozygous TUBB3 pathogenic variants. We compared these patients with other published TUBB3-related cases. We describe the pathological features of dysgyria in the two aborted fetuses.

Results: The mother and son from family 1 had a history of mild developmental delay in motor and language skills and demonstrated mild cerebellar signs and mirror movements. Neuroimaging findings included: hypoplastic corpus callosum (CC), asymmetric ventriculomegaly and cerebellar vermis hypoplasia in all patients and frontal dysgyria in three. Autopsy of the fetal brain showed an unusual shape and orientation of the frontal sulci and gyri with normal cortical layering and no abnormal cell types. The mother of family 2 had congenital strabismus, mild muscle weakness on the right and a past history of developmental delay. Fetal brain MRI showed abnormal cerebral sulcation, hemispheric asymmetry, asymmetric ventriculomegaly, dysmorphic short CC and frontal cortical interdigitation. Autopsy demonstrated fronto-parietal predominant dysgyria, bilateral ventriculomegaly, hippocampal and CC hypoplasia, abnormal Sylvian fissure. Lamination and neuron morphology in the areas of dysgyria were normal.

Conclusions: TUBB3 related cortical malformations can be mild, consistent with dysgyria rather than typical pachygyria or polymicrogyria. The autopsy findings in fetal TUBB3 related dysgyria are abnormal orientation of sulci and gyri, but normal neuron morphology and layering. We suggest that TUBB3 - associated brain malformations can be suspected in-utero which in turn can aid in prognostic counselling and interpretation of genetic testing.
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http://dx.doi.org/10.1016/j.ejpn.2020.03.001DOI Listing
May 2020

Agenesis of the septum pellucidum: Prenatal diagnosis and outcome.

Prenat Diagn 2020 05 31;40(6):674-680. Epub 2020 Mar 31.

Division of Ultrasound in Obstetrics & Gynecology, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Israel and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Objective: The purpose of this study is to describe the imaging findings in a group of fetuses with suspected agenesis of the septum pellucidum (ASP) and to evaluate their clinical outcome.

Methods: This is a retrospective multicenter study on a cohort of fetuses diagnosed with suspected ASP, between 2008 and 2017. The records of each patient, including ultrasound (US) and magnetic resonance studies, were reviewed and compared with the postnatal findings.

Results: Forty-seven patients were included in the study at a mean gestational age of 26.6 weeks. In 17 patients, the ASP was considered isolated. Fourteen patients delivered live-born, and all 14 are developing normally. Three were lost to follow-up. Twenty-four patients had associated malformations involving the central nervous system (CNS); 13 were delivered (normal development [5], abnormal [6] and no follow-up [2]). Nine patients opted for termination, and two pregnancies were lost to follow-up. Six patients had non-CNS associated findings, two were delivered with normal neurological development and four had a termination.

Conclusions: Isolated ASP is usually associated with a favorable outcome; but in the presence of associated malformations, there is at least a 50% risk of abnormal development. Current imaging techniques can provide an accurate prognosis in cases when ASP appears isolated.
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http://dx.doi.org/10.1002/pd.5663DOI Listing
May 2020

Subtle findings on fetal brain imaging in CMV infected pregnancies: What is the clinical significance? A retrospective analysis with outcome correlation.

Prenat Diagn 2020 03 24;40(4):447-453. Epub 2020 Feb 24.

OB-GYN Ultrasound Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Objective: To describe the prognosis of subtle findings on fetal brain imaging in pregnant women with primary CMV infection during pregnancy.

Methods: This was a retrospective study. The data included: timing of infection, amniocentesis results, imaging findings, obstetric outcome, and developmental assessment.

Results: For the 27 included patients, the time of infection was: periconception, first, second, third trimesters or unknown in 14.8%, 29.7%, 40.7%, 7.4%, and 7.4%, respectively. Seventy-four percent had only MRI findings; white matter hyperintense T2 signal (HT2) (51.8%), mild ventriculomegaly (18.5%), HT2 and temporal cyst (7.4%), dilated occipital horn (7.4%), Periventricular pseudo cyst (PVPC) with dilated occipital horn (3.7%), isolated PVPC (7.4%), choroid plexus cyst (3.7%). In 26% of fetuses, additional ultrasound findings were observed: Lenticulostriatal vasculopathy (LSV) (11.1%), LSV with PVPC (3.84%), isolated PVPC (3.84%), mild ventriculomegaly (3.84%), and bilateral temporal cysts (3.84%). In 66.6%, the MRI had false-positive findings (due to noninfected neonates). All children are developing normally, and one has a hearing deficit. Postnatal ultrasound (US) was normal in 21/27, with LSV in five, and a resolving subependymal cyst in one patient.

Conclusion: Subtle imaging findings are more common on MRI than US and the prognosis is most likely favorable. Performing amniocentesis will significantly reduce the false-positive rate.
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http://dx.doi.org/10.1002/pd.5634DOI Listing
March 2020

Surgical Management of "Kissing" Spinal Plexiform Neurofibromas in Neurofibromatosis Type 1 Patients.

World Neurosurg 2020 Feb 28;134:e1143-e1147. Epub 2019 Nov 28.

The Gilbert Israeli Neurofibromatosis Center, Tel-Aviv Medical Center, and Tel-Aviv University, Tel-Aviv, Israel; Department of Pediatric Neurosurgery, Tel-Aviv Medical Center, and Tel-Aviv University, Tel-Aviv, Israel. Electronic address:

Background: "Kissing" neurofibromas (KNs) are a unique group of spinal tumors found in neurofibromatosis type 1 (NF1) patients. These are bilateral neurofibromas that approximate each other at the same level, with significant impingement compression of the cord or thecal sac. The best management options and surgical strategies for NF1 patients with KN have not been standardized.

Methods: We conducted a retrospective study evaluating adult NF1 patients with KN. All patients are followed routinely at the Gilbert Israeli NF Center. Patients' files were reviewed for natural history, imaging features, surgical technique, and surgical outcome.

Results: Twelve patients with at least 1 pair of KN were identified (6 females). Median age at spinal presentation was 24 (range 17-48). KNSs were located at the cervical (n = 8) and lumbar (n = 8) region, with no thoracic involvement. Seven of the 12 patients were operated; all underwent surgery due to cervical compression with progressive myelopathy. Four patients remained asymptomatic during the follow-up period. Three patients underwent multiple operations. Operative outcome was favorable in 71% of patients, with marked overall motor improvement or stabilization of neurologic deterioration. Two patients who entered surgery with a low functional reserve deteriorated after surgery.

Conclusions: In our series, KN caused progressive cord compression in 7 of the 8 patients with cervical tumors. No intervention was needed for lumbar tumors. Cervical tumors should be followed closely, with a low threshold for intervention. NF1 patients harboring KN should be followed both clinically and radiologically for life.
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http://dx.doi.org/10.1016/j.wneu.2019.11.124DOI Listing
February 2020

The role of screening spinal MRI in children with solitary posterior fossa low-grade glial tumors.

J Neurosurg Pediatr 2019 Nov 15:1-5. Epub 2019 Nov 15.

1Department of Pediatric Neurosurgery and.

Objective: Solitary posterior fossa low-grade glial tumors (SPFLGT) in children are rarely associated with leptomeningeal dissemination (LMD). To date, there are no clear guidelines regarding the role of screening and surveillance spinal MRI (sMRI) in children with SPFLGT, at diagnosis or during follow-up periods. The current study reviews a cohort of children with SPFLGT, focusing on sMRI findings.

Methods: In this binational retrospective study, the authors analyzed 229 patients with SPFLGT treated and followed over 13 years. One hundred twelve children had at least 1 total sMRI screening or surveillance examination. One hundred seventeen had no sMRI, but did not present with clinical spinal signs or symptoms. Collected data included demographics, disease characteristics, radiology, pathology, and clinical follow-up data.

Results: For the 112 children with at least 1 sMRI, the mean duration from diagnosis to first sMRI was 11.73 ± 28.66 months (range 0-165 months). All sMRI scans were conducted as screening examinations, with no spinal-related symptoms. One patient was found to have a sacral intradural lesion concurrent to the brain tumor diagnosis. Over the course of 180 radiological and 533 clinical follow-up years for the 112 patients with sMRI, and 582 clinical follow-up years for the 117 patients with no sMRI, there were no additional cases with spinal tumor spread.

Conclusions: The yield of screening sMRI in the absence of cranial metastasis, or spinal symptoms, is extremely low. Because preoperative sMRI is recommended for medulloblastomas and ependymomas, it may be logical to acquire. During the follow-up period the authors recommend limiting sMRI in patients without symptoms suggesting a spinal lesion, in patients without known cranial metastases, or recurrence or residual SPFLGT.
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http://dx.doi.org/10.3171/2019.9.PEDS19358DOI Listing
November 2019

Brain white matter abnormalities associated with copy number variants.

Am J Med Genet A 2020 01 17;182(1):93-103. Epub 2019 Oct 17.

Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel.

White matter (WM) signal abnormalities are demonstrated in various neurodevelopmental disorders on brain magnetic resonance imaging (MRI). The pattern of WM abnormalities can aid in the diagnostic process. This study aims to characterize the WM changes found in microdeletion/microduplication syndromes. Thirteen patients with neurodevelopmental disorders due to copy number variations were collected from a cohort of children with evidence of WM abnormalities on brain MRI, in two medical centers. A pediatric neuroradiologist blindly interpreted the MRI scans. Clinical and genetic findings were retrospectively extracted from the medical records. WM changes included: multifocal (10/13) periventricular (12/13) and subcortical (5/13) signal abnormalities and WM volume loss (6/13). Dysgenesis of the corpus callosum was depicted in 12/13. The main clinical features were: global developmental delay (13/13), hypotonia (11/13), epilepsy (10/13), dysmorphic features (9/13), microcephaly (6/13), short stature (6/13), and systemic involvement (6/13). We showed that different chromosomal micro-rearrangement syndromes share similar MRI patterns of nonspecific multifocal predominantly periventricular WM changes associated with corpus callosum dysgenesis with or without WM and gray matter loss. Hence, the association of these features in a patient evaluated for global developmental delay/intellectual disability suggests a chromosomal micro-rearrangement syndrome, and a chromosomal microarray analysis should be performed.
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http://dx.doi.org/10.1002/ajmg.a.61389DOI Listing
January 2020

Mature teratoma splitting the brainstem in a newborn: case report.

J Neurosurg Pediatr 2019 Jul 26:1-5. Epub 2019 Jul 26.

4Department of Pediatric Neurosurgery, Dana Children's Hospital, Tel-Aviv Medical Center, Tel-Aviv University, Tel-Aviv, Israel.

Mature teratomas (MTs) of the posterior fossa are extremely rare. The authors present a case of a prenatal diagnosis of an MT splitting the brainstem. Representative images as well as the clinical and surgical course are presented. Literature regarding "split brainstem" and MT of the posterior fossa is discussed.
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http://dx.doi.org/10.3171/2019.5.PEDS19142DOI Listing
July 2019

Autism-associated Nf1 deficiency disrupts corticocortical and corticostriatal functional connectivity in human and mouse.

Neurobiol Dis 2019 10 22;130:104479. Epub 2019 May 22.

Department of Neuroscience, Rappaport Faculty of Medicine and Institute, Technion - Israel Institute of Technology, Haifa, Israel. Electronic address:

Children with the autosomal dominant single gene disorder, neurofibromatosis type 1 (NF1), display multiple structural and functional changes in the central nervous system, resulting in neuropsychological cognitive abnormalities. Here we assessed the pathological functional organization that may underlie the behavioral impairments in NF1 using resting-state functional connectivity MRI. Coherent spontaneous fluctuations in the fMRI signal across the entire brain were used to interrogate the pattern of functional organization of corticocortical and corticostriatal networks in both NF1 pediatric patients and mice with a heterozygous mutation in the Nf1 gene (Nf1). Children with NF1 demonstrated abnormal organization of cortical association networks and altered posterior-anterior functional connectivity in the default network. Examining the contribution of the striatum revealed that corticostriatal functional connectivity was altered. NF1 children demonstrated reduced functional connectivity between striatum and the frontoparietal network and increased striatal functional connectivity with the limbic network. Awake passive mouse functional connectivity MRI in Nf1 mice similarly revealed reduced posterior-anterior connectivity along the cingulate cortex as well as disrupted corticostriatal connectivity. The striatum of Nf1 mice showed increased functional connectivity to somatomotor and frontal cortices and decreased functional connectivity to the auditory cortex. Collectively, these results demonstrate similar alterations across species, suggesting that NF1 pathogenesis is linked to striatal dysfunction and disrupted corticocortical connectivity in the default network.
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http://dx.doi.org/10.1016/j.nbd.2019.104479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689441PMC
October 2019

Metabolic stroke in a patient with bi-allelic OPA1 mutations.

Metab Brain Dis 2019 08 10;34(4):1043-1048. Epub 2019 Apr 10.

Metabolic Neurogenetic Service, Pediatric Neurology Unit, Wolfson Medical Center, Halochamim 62, Holon, Israel.

OPA1 related disorders include: classic autosomal dominant optic atrophy syndrome (ADOA), ADOA plus syndrome and a bi-allelic OPA1 complex neurological disorder. We describe metabolic stroke in a patient with bi-allelic OPA1 mutations. A twelve-year old girl presented with a complex neurological disorder that includes: early onset optic atrophy at one year of age, progressive gait ataxia, dysarthria, tremor and learning impairment. A metabolic stroke occurred at the age of 12 years. The patient was found to harbor a de novo heterozygous frame shift mutation c.1963_1964dupAT; p.Lys656fs (NM_015560.2) and a missense mutation c.1146A > G; Ile382Met (NM_015560.2) inherited from her mother. The mother, aunt, and grandmother are heterozygous for the Ile382Met mutation and are asymptomatic. The co-occurrence of bi-allelic mutations can explain the severity and the early onset of her disease. This case adds to a growing number of patients recently discovered with bi-allelic OPA1 mutations presenting with a complex and early onset neurological disorder resembling Behr syndrome. To the best of our knowledge metabolic stroke has not been described before as an OPA1 related manifestation. It is important to be aware of this clinical feature for a prompt diagnosis and consideration of available treatment.
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http://dx.doi.org/10.1007/s11011-019-00415-2DOI Listing
August 2019