Congenital Brain Malformations Research Articles

Cerebral palsy in children: a clinical overview.

Cerebral palsy (CP) is a disorder characterized by abnormal tone, posture and movement and clinically classified based on the predominant motor syndrome—spastic hemiplegia, spastic diplegia, spastic quadriplegia, and extrapyramidal or dyskinetic. The incidence of CP is 2–3 per 1,000 live births. Prematurity and low birthweight are important risk factors for CP; however, multiple other factors have been associated with an increased risk for CP, including maternal infections, and multiple gestation. In most cases of CP the initial injury to the brain occurs during early fetal brain development; intracerebral hemorrhage and periventricular leukomalacia are the main pathologic findings found in preterm infants who develop CP. The diagnosis of CP is primarily based on clinical findings. Early diagnosis is possible based on a combination of clinical history, use of standardized neuromotor assessment and findings on magnetic resonance imaging (MRI); however, in most clinical settings CP is more reliably recognized by 2 years of age. MRI scan is indicated to delineate the extent of brain lesions and to identify congenital brain malformations. Genetic tests and tests for inborn errors of metabolism are indicated based on clinical findings to identify specific disorders. Because CP is associated with multiple associated and secondary medical conditions, its management requires a multidisciplinary team approach. Most children with CP grow up to be productive adults.

Magnetic resonance imaging findings in patients with cerebral palsy in Duhok, Iraq: Case series

Aim: Magnetic resonance imaging is an important technique for evaluating structural abnormalities in the brain. Many neurologists and pediatricians refer cerebral palsy patients to conventional magnetic resonance imaging. The objective of this study was to assess magnetic resonance imaging findings in children with cerebral palsy and to research whether it can predict the etiology or pathogenesis of this disease.Methods: This case study was carried out at Azadi General Hospital from the 1st of July 2016 until the 28th of February 2017. A total of 48 patients who were diagnosed with cerebral palsy were included in the study. They all underwent cranial magnetic resonance imaging under general anaesthesia, and results were compared statistically. Results: The male to female ratio was 2.4:1. Magnetic resonance imaging was abnormal in 87.5%. Diffuse encephalopathy was seen in 56.2% of cases, periventricular leukomalacia was detected in 18.8%, changes of ischemic lesion were seen in 4.2 %, congenital malformations in 8.3% and normal scan was seen in 12.5% of cases. Among the clinical sub-types of cerebral palsy, spastic diplegia was the most common (47.9%), followed by spastic quadriplegia (35.4%), spastic hemiplegia (10.4%), and choreoathetoid cerebral palsy (6.3%). Conclusions: This study concluded that brain changes in magnetic resonance imaging can detect the pathogenesis of cerebral palsy and is diagnostic in congenital brain malformations.

A Complex Cortical Malformation Caused by a Mutation in the Tubulin-Encoding TUBB3 Gene

Tubulinopathy commonly refers to complex congenital and non-progressive brain malformations caused by mutations in the tubulin genes. Among tubulin-encoding genes, TUBB3 has rarely been reported as a cause of complex cortical malformations. Herein, we report a case of tubulinopathy in a 21-month-old boy who presented with delayed development. He could not walk on his own and was not able to speak more than five words. Physical examination revealed right esotropia and hypotonia of the lower extremities. MRI showed dysmorphic brainstem and dysmorphic and hypertrophic basal ganglia. The right thalamus was relatively smaller than the left one. The cerebellum showed disorganization of the cerebellar folia. DNA sequencing revealed a missense mutation of the TUBB3 gene.

EML1-associated brain overgrowth syndrome with ribbon-like heterotopia.

EML1 encodes the protein Echinoderm microtubule‐associated protein‐like 1 or EMAP‐1 that binds to the microtubule complex. Mutations in this gene resulting in complex brain malformations have only recently been published with limited clinical descriptions. We provide further clinical and imaging details on three previously published families, and describe two novel unrelated individuals with a homozygous partial EML1 deletion and a homozygous missense variant c.760G>A, p.(Val254Met), respectively. From review of the clinical and imaging data of eight individuals from five families with biallelic EML1 variants, a very consistent imaging phenotype emerges. The clinical syndrome is characterized by mainly neurological features including severe developmental delay, drug‐resistant seizures and visual impairment. On brain imaging there is megalencephaly with a characteristic ribbon‐like subcortical heterotopia combined with partial or complete callosal agenesis and an overlying polymicrogyria‐like cortical malformation. Several of its features can be recognized on prenatal imaging especially the abnormaly formed lateral ventricles, hydrocephalus (in half of the cases) and suspicion of a neuronal migration disorder. In conclusion, biallelic EML1 disease‐causing variants cause a highly specific pattern of congenital brain malformations, severe developmental delay, seizures and visual impairment.

Prenatal or Perinatal Injury? Diagnosing the Cortically Blind Infant

To document the association of prenatal brain disruption with secondary perinatal distress in children diagnosed as having cortical visual impairment (CVI). Retrospective case series. Eight children with severe CVI and clinical history of perinatal events were included. Case histories and neuroimaging studies were reviewed. The main outcome measures were perinatal history, visual and neurologic findings, and magnetic resonance (MR) imaging. In our patient cohort, MR imaging showed signs of cortical dysgenesis leading to congenital brain malformations such as polymicrogyria consistent with a prenatal timing of CNS injury. Although subcortical white matter changes were common, signs of watershed injury to the visual cortex were absent, suggesting that the visual loss was attributable to a prenatal etiology with secondary birth complications. Some children with CVI and a history of perinatal distress have prenatal dysgenesis of the developing brain. Therefore, a clinical history of perinatal hypoxia-ischemia is nonspecific and merits neuroimaging to identify antecedent brain malformations and timing of injury, which can influence patient diagnosis and management.

Anterior and posterior commissures in agenesis of the corpus callosum: Alternative pathways for attention processes?

Developmental absence (agenesis) of the corpus callosum (AgCC) is a congenital brain malformation resulting from disruption of corpus callosum formation, a structure that is crucial for the transfer and integration of information, including attention processes, across the brain. This study aimed to investigate previously proposed candidates for alternative inter-hemispheric pathways in AgCC by examining (1) white matter volume and microstructure of the anterior and posterior commissures in children with AgCC compared to typically developing controls (TDC), and (2) in children with AgCC, examine the associations of white matter volume and microstructure of the anterior and posterior commissures and any remaining corpus callosum with attention processes. Participants were 21 children with AgCC (13 complete, 8 partial) recruited from The Royal Children's Hospital, Melbourne, and 30 TDC aged 8–17 years. T1-and diffusion-weighted MR sequences were used to calculate volume and microstructural parameters. Neuropsychological testing assessed attention processes. We found the anterior commissure was significantly larger in volume in children with AgCC than TDC (p = .027), with reduced mean FA (p = .001) associated with increased mean RD (p < .001). In children with AgCC, we found microstructural properties of the anterior commissure associated with attentional processes, specifically, mean FA of the anterior commissure was associated with better divided attention (p = .03), and the association between alerting attention and mean AD and RD was found to be moderated by age (p = .027, p = .008) and the degree of corpus callosum agenesis (p = .025, p = .016). Furthermore, in partial AgCC, larger posterior commissure volume was associated with better orienting attention (p = .035). In conclusion, we provide evidence that the volume and microstructure of the anterior commissure are altered in children with AgCC, and this neuroplastic response might have an influence on attention processes.

Brain Embryology and Congenital Brain Malformations: Conventional and Advanced Neuroimaging

Brain Embryology and Congenital Brain Malformations: Conventional and Advanced Neuroimaging

Brain Embryology and Congenital Brain Malformations: Conventional and Advanced Neuroimaging

Brain Embryology and Congenital Brain Malformations: Conventional and Advanced Neuroimaging

Fetal MRI in Prenatal Diagnosis of Encephalocele

Encephalocele, a rare congenital brain malformation, is herniation of brain tissue with or without meninges through a cranial fossa defect. It is classified by location and is usually associated with other congenital anomalies. A 29-year-old G2, P1, 36-week pregnant woman was referred for fetal ultrasound delivery planning. Sonographic abnormalities led to fetal magnetic resonance imaging, which revealed a large sac of cerebrospinal fluid herniating through the anterior cranial fossa defect with strands of neurogenic tissue in direct contact with the tongue in the absence of the palate. Agenesis of the corpus callosum and the classic "Viking helmet" appearance of the frontal horns of the lateral ventricles were clearly visible. Prenatal diagnosis of encephalocele is rarely reported. Unfortunately, the infant in this case report died at 3 months of age despite intensive medical therapy.

Fetal brain MRI findings and neonatal outcome of common diagnosis at a tertiary care center.

Identify common brain malformations on fetal MRI and evaluate perinatal course. Fetal consultations from 10/2016 to 12/2017 reviewed. Hundred consultations were requested; 94 were completed. Findings included: posterior fossa malformations (19%), agenesis/dysgenesis of corpus callosum (15%), congenital aqueductal stenosis (CAS) (14%), ventriculomegaly (11%), isolated cortical malformations (8.5%), and holoprosencephaly (6%). Posterior fossa malformations were more likely to be associated with genetic conditions and cardiac malformations. Patients with CAS all required intensive care unit admission. Overall, few patients with congenital brain malformations required feeding or respiratory support at discharge. None had seizures as neonates except two with early epileptic encephalopathy syndromes. Even though long term neurological prognosis is poor for many conditions including high lifetime risk of epilepsy, most are discharged with no feeding or respiratory support. Seizures are rarely seen in the neonatal period.

Connectomics in Brain Malformations: How Is the Malformed Brain Wired?

A new neuroimaging dimension is currently being adopted. The structural connectome reveals macroscale white matter connectivity of the human brain, providing insights into brain networks organization. Connectomics (analysis of the connectome) has potential for elucidating aberrant networks (eg, in congenital brain malformations, especially axonal pathfinding disorders). Connectomics provides a powerful set of network measures, which can serve as noninvasive biomarkers for the diagnosis, prognostication, and treatment response of children. We discuss the principles of connectome reconstruction and visualization of the pediatric structural connectome using current state-of-the-art neuroimaging and postprocessing techniques, and we describe potential connectomics applications to study brain malformations.

White Matter Lesions Detected by Magnetic Resonance Imaging in Neonates and Children With Congenital Myotonic Dystrophy

BackgroundCongenital myotonic dystrophy (CDM1) is an autosomal dominant genetic disorder caused by abnormal cytosine-thymine-guanine trinucleotide repeat expansion that results in weakness and cognitive deficits. Studies detailing brain magnetic resonance imaging (MRI) findings in neonates and children with this condition are limited. ObjectiveWe evaluated the brain MRI findings in children, including neonates with CDM1, to assess the nature of central nervous system involvement and progression of MRI lesions over time. MethodsThe Cincinnati Children's Hospital neuromuscular disease database was used to identify 16 patients with CDM1 with genetically proven CDM1 who had undergone brain MRI. Hospital charts were reviewed to collect clinical information. ResultsNinety-four percent of patients had an abnormal MRI showing injury to the white matter. Nine patients underwent imaging before eight days of life, and eight of these patients showed signs of injury to the white matter. Three neonates had follow-up MRI scans, and all showed progression of injury. Seven patients had the first MRI between age 29 days and 22 years, and all had abnormalities involving the white matter. Two patients had additional congenital brain malformations, and one patient also harbored a mutation in CDKL5 with resultant epilepsy. ConclusionsWhite matter abnormalities are found in patients with CDM1, even in the neonatal period. Many patients present with hypoxia and receive a diagnosis of hypoxic-ischemic encephalopathy and may even undergo therapeutic hypothermia. If MRI findings of white matter injury do not correlate with hypotonia and weakness, further evaluation for CDM1 should be considered.

Dandy-Walker malformation in Polish hunting dogs: long term prognosis and quality of life

In the last few years, it has become easier to diagnose congenital brain malformations in dog’s ante-mortem. This is probably due to the wider availability of advanced diagnostic imaging, in particular computed tomography or magnetic resonance imaging (MRI). Despite this, there is still not much literature available about potential treatments, outcome and overall prognosis with respect to the patient’s quality of life. We present three cases of Dandy-Walker malformation in Polish hunting dogs with up to five years follow up including assessment of their quality of life. A nine-week-old Polish hunting dog was presented with progressive signs of ataxia that had developed over the preceding few weeks. MRI revealed a Dandy-Walker malformation. The dog underwent MRI at the ages of 12 and 36 months, and his neurological condition was followed for five years. No other subsequent abnormities were found on further diagnostic tests. The dog showed transient behavioural problems which improved after castration and training. The ataxia seen at first visit improved with time and intensive physiotherapy, and the dog was considered to have a good quality of life in the owner’s eyes. A further two cases shared a similar disease course. Dandy-Walker malformation was confirmed with MRI, but diagnostic imaging could not be reported here because the owner did not consent to publication. The Dandy-Walker malformations described in these three Polish hunting dogs had a stable disease course and revealed that dogs suffering from this condition may have a good quality of life, providing no other abnormalities are detected and rehabilitation is performed.

Chapter 5 - Fetal and neonatal neurogenetics

Disorders of the developing nervous system may be of genetic origin, comprising congenital malformations of spine and brain as well as metabolic or vascular disorders that affect normal brain development. Acquired causes include congenital infections, hypoxic-ischemic or traumatic brain injury, and a number of rare neoplasms. This chapter focuses on the clinical presentation and workup of neurogenetic disorders presenting in the fetal or neonatal period. After a summary of the most frequent clinical presentations, clues from history taking and clinical examination are illustrated with short case reports. This is followed by a discussion of the different tools available for the workup of neurogenetic disorders, including the various genetic techniques with their advantages and disadvantages. The implications of a molecular genetic diagnosis for the patient and family are addressed in the section on counseling. The chapter concludes with a proposed workflow that may help the clinician when confronted with a potential neurogenetic disorder in the fetal or neonatal period.

Hypothalamic Obesity: 4 Years of the International Registry of Hypothalamic Obesity Disorders.

Hypothalamic obesity (HyOb) is a rare cause of rapid weight gain and early metabolic comorbidities. Effective treatment strategies are limited. The registry collected participant data and compared treatment approaches. The International Registry of Hypothalamic Obesity Disorders (IRHOD) was created as a registry portal to provide education. Data collected from the initial 4 years were evaluated. Eighty-seven participants were included for analysis (median age: 27 years, range: 3-71 years). A total of 96.5% had obesity, and 3.5% had overweight at maximal weight. Seventy-five had brain tumors (86%)-the majority were craniopharyngiomas (72% of those with tumors). Nontumor etiologies included congenital brain malformation (4.6%), traumatic brain injury (3.4%), and genetic anomaly (2.3%). Ninety percent received obesity treatments including nutritional counseling (82%), pharmacotherapy (59%), bariatric surgery (8%), and vagal nerve stimulation (1%). Forty-six percent reported follow-up BMI results after obesity treatment. Surgery was most effective (median BMI decrease: -8.2 kg/m2 , median interval: 2.6 years), with lifestyle intervention (BMI: -3.4 kg/m2 , interval: 1.2 years) and pharmacological therapy (BMI: -2.3 kg/m2 , interval: 0.8 years) being less effective. Eighty percent of participants reporting follow-up weight remained in the obesity range. IRHOD identified a large cohort with self-reported HyOb. Surgical therapy was most effective at weight reduction. Nutritional counseling and pharmacotherapy modestly improved BMI. Stepwise treatment strategy for HyOb (including nutritional, pharmacological, and surgical therapies in an experienced center) may be most valuable.

Comparative Neuropathology of Major Indian Bluetongue Virus Serotypes in a Neonatal BALB/c Mouse Model

Bluetongue virus (BTV) is neurotropic in nature, especially in ruminant fetuses and in-utero infection results in abortion and congenital brain malformations. The aim of the present study was to compare the neuropathogenicity of major Indian BTV serotypes 1, 2, 10, 16 and 23 by gross and histopathological lesionsand virus distribution in experimentally infected neonatal BALB/c mice. Each BTV serotype (20μl of inoculum containing 1×105 tissue culture infectious dose [TCID]50/ml of virus) was inoculated intracerebrally into 3-day-old mice, while a control group was inoculated with mock-infected cell culture medium. Infection with BTV serotypes 1, 2 and 23 led to 65-70% mortality at 7-9 days post infection (dpi) and caused severe necrotizing encephalitis with neurodegenerative changes in neurons, swelling and proliferation of vascular endothelial cells in the cerebral cortex, cerebellum, midbrain and brainstem. In contrast, infection with BTV serotypes 10 and 16 led to 25-30% mortality at 9-11 dpi and caused mild neuropathological lesions. BTV antigen was detected by immunohistochemistry, direct fluorescence antibody technique and confocal microscopy in the cytoplasm of neuronal cells of the hippocampus, grey matter of the cerebral cortex and vascular endothelial cells in the midbrainand brainstem of BTV-1, -2, -10, -16 and -23 infected groups from 3 to 20 dpi. BTV nucleic acid was detected in the infected brain tissues from as early as 24h up to 20 dpi by VP7 gene segment-based one-step reverse transcriptase polymerase chain reaction. This study of the relative neurovirulence of BTV serotypes is likely to help design suitable vaccination and control strategies for the disease.

Dandy –Walker Malformation with Patent Ductus Arteriosus– A Case Report

Dandy–Walker malformation (DWM) is a group of congenital human brain malformation with specific characteristics. It may be associated with a number of other organ malformation including heart, eye, and thyroid glands. In our case, DWM was associated with heart malformation in the form of patent ductus arteriosus (PDA) and was complicated by atrial fibrillation. The case was established by computed tomography of brain, echocardiography and electrocardiography. The patient was asymptomatic until 7 years of age.J Bangladesh Coll Phys Surg 2018; 36(3): 128-131

A Neuropsychological Profile for Agenesis of the Corpus Callosum? Cognitive, Academic, Executive, Social, and Behavioral Functioning in School-Age Children.

Agenesis of the corpus callosum (AgCC), characterized by developmental absence of the corpus callosum, is one of the most common congenital brain malformations. To date, there are limited data on the neuropsychological consequences of AgCC and factors that modulate different outcomes, especially in children. This study aimed to describe general intellectual, academic, executive, social and behavioral functioning in a cohort of school-aged children presenting for clinical services to a hospital and diagnosed with AgCC. The influences of age, social risk and neurological factors were examined. Twenty-eight school-aged children (8 to 17 years) diagnosed with AgCC completed tests of general intelligence (IQ) and academic functioning. Executive, social and behavioral functioning in daily life, and social risk, were estimated from parent and teacher rated questionnaires. MRI findings reviewed by a pediatric neurologist confirmed diagnosis and identified brain characteristics. Clinical details including the presence of epilepsy and diagnosed genetic condition were obtained from medical records. In our cohort, ~50% of children experienced general intellectual, academic, executive, social and/or behavioral difficulties and ~20% were functioning at a level comparable to typically developing children. Social risk was important for understanding variability in neuropsychological outcomes. Brain anomalies and complete AgCC were associated with lower mathematics performance and poorer executive functioning. This is the first comprehensive report of general intellectual, academic, executive social and behavioral consequences of AgCC in school-aged children. The findings have important clinical implications, suggesting that support to families and targeted intervention could promote positive neuropsychological functioning in children with AgCC who come to clinical attention. (JINS, 2018, 24, 445-455).

Application of Clinical Next Generation Sequencing in Intensive Care Facilitates Rapid Diagnosis of Neonates with Rare Genetic Disorders

Background: Neonatal muscular hypotonia is a common clinical feature on neonatal intensive care units with a broad spectrum of etiologies. Besides more common and obvious underlying conditions like prematurity or Down syndrome many rare disorders with often poor prognosis need to be considered. Congenital brain malformations detected on ultrasound or/and magnetic resonance imaging might constitute the clinical hallmark in differential diagnosis. We report on our approach combining cerebral imaging and application of targeted next generation panel sequencing. Methods: Retrospective review and evaluation of patients´ files and cerebral images of 4 severely affected neonates treated at the neonatal intensive care unit of our university children’s hospital in 2016 with confirmed genetic diagnosis using clinically targeted multi gene panel sequencing and/or Sanger sequencing. Results: Detailed presentation of the phenotype and genotype of 4 neonates with muscular hypotonia and abnormal MR imaging due to genetically confirmed Aicardi-Goutieres syndrome (TREX1), Zellweger spectrum disorder (PEX13), Pontocerebellar Hypoplasia (TSEN54) and X-linked Hydrocephalus (L1CAM), respectively. Overview of genetic and metabolic disorders with brain malformations presenting with neonatal onset muscular hypotonia as a leading symptom. Conclusions: Comprehensive multidisciplinary clinical evaluation of patients with neonatal muscular hypotonia allows phenotype based individual genetic testing including novel targeted multi gene panel testing. This approach might ultimately improve the turn-around time and diagnostic yield including a wide range of very rare genetic disorders.

Using immunocompromised mice to identify mechanisms of Zika virus transmission and pathogenesis.

Zika virus (ZIKV) is responsible for a recent global epidemic that has been associated with congenital brain malformations in fetuses and with Guillain-Barré syndrome in adults. Within the last 2years, a major effort has been made to develop murine models to study the mechanism of viral transmission, pathogenesis and the host immune response. Here, we discuss the findings from these models regarding the role that the innate and adaptive immune responses have in controlling ZIKV infection and pathogenesis. Additionally, we examine how innate and adaptive immune responses influence sexual and vertical transmission of ZIKV infection as well as how these responses can influence the ability of ZIKV to cross the placenta and to induce damage in the developing brain.