Crosstalk between Microglia and Neurons in Neurotrauma: An Overview of the Underlying Mechanisms

: Microglia are the resident immune cells of the brain and play a crucial role in housekeeping and maintaining homeostasis of the brain microenvironment. Upon injury or disease, microglial cells become activated, at least partly, via signals initiated by injured neurons. Activated microglia, thereby, contribute to both neuroprotection and neuroinflammation. However, sustained microglial activation initiates a chronic neuroinflammatory response which can disturb neuronal health and disrupt communications between neurons and microglia. Thus, microglia-neuron crosstalk is critical in a healthy brain as well as during states of injury or disease. As most studies focus on how neurons and microglia act in isolation during neurotrauma, there is a need to understand the interplay between these cells in brain pathophysiology. This review highlights how neurons and microglia reciprocally communicate under physiological conditions and during brain injury and disease. Furthermore, the modes of microglia-neuron communication are exposed, focusing on cell-contact dependent signaling and communication by the secretion of soluble factors like cytokines and growth factors. In addition, how microglia-neuron interactions could exert either beneficial neurotrophic effects or pathologic proinflammatory responses are discussed. We further explore how aberrations in microglia-neuron crosstalk may be involved in central nervous system (CNS) anomalies, namely: traumatic brain injury (TBI), neurodegeneration, and ischemic stroke. A clear understanding of how the microglia-neuron crosstalk contributes to the pathogenesis of brain pathologies may offer novel therapeutic avenues of brain trauma treatment.

Applicability of a Semiautomated Volumetric Approach (5D CNS+™) for Detailed Antenatal Reconstruction of Abnormal Fetal CNS Anatomy

Background. The aim of this study was to evaluate the accuracy and reliability of a semiautomated volumetric approach (5DCNS+) when examining fetuses with an apparent abnormal anatomy of the central nervous system (CNS).Methods. Stored 3D volumes of 91 fetuses with structural cerebral anomalies extracted from a cohort of >1.400 consecutive 2nd and 3rd trimester pregnancies (range 15-36 gestational weeks) were analyzed using the semiautomatic software tool 5DCNS+, enabling detailed reconstruction of nine diagnostic planes of the fetal brain. All 3D data sets were examined and judged for plane accuracy, the need for manual adjustment, and fetal CNS anomalies affecting successful plane reconstruction.Results. Based on our data, we were able to reveal a wide range of CNS anomalies with application of the 5DCNS+ technique. The corresponding anatomical features and consecutive changes of neighboring structures could be clearly demonstrated. Thus, a profound assessment of the entire altered CNS anatomy could be achieved in nearly all cases. The comparison with matched controls showed a significant difference in volume acquisition (p <0.001) and in need for manual adjustment (p < 0.001) but not in the drop-out rates (p = 0.677) of both groups.Conclusion. 5DCNS+ software is applicable in the majority of cases with brain lesions and constitutes a reliable tool even if the integrity of the fetal CNS is compromised by structural anomalies. Using volume data that were acquired in identical cutting sections needed for conventional biometry allows for detailed anatomic surveys grossly independent of the examiner’s experience.

Predicting outcomes in Dandy-Walker malformation: a retrospective cohort study

OBJECTIVE Dandy-Walker malformation (DWM) is a disorder that most neurologists and neurosurgeons will manage at some point during their careers. It is characterized by partial or complete dysgenesis of the cerebellar vermis. Outcomes are highly variable and range from functionally normal to severely disabled. Predicting these outcomes has classically been focused on the radiological findings that constitute DWM. Other anomalies that can be commonly found in these patients are potentially more indicative of outcome than the tenet markers of DWM. Furthermore, hydrocephalus is an ever-present danger in these patients, many of whom will be admitted to the hospital due to this condition. This study aims to identify these items as potential predictors of outcome. METHODS All referrals from antenatal anatomy scans between 1992 and 2013 that were suspicious for DWM were reviewed. Neurosurgery archives were reviewed for outpatient letters and other correspondence. The number of DWM diagnoses was quantified. Outcomes were judged based on patient status, ranging from death to attending normal school. The presence of any other anomalies was quantified and measured against patient outcomes. RESULTS Cyst size and the presence of another CNS anomaly were shown to portend worse outcomes. Non-CNS anomalies and hydrocephalus were not predictive of worse outcomes. Furthermore, of all the treatments assessed, ventriculoperitoneal shunts were shown to be the most effective in this data set. CONCLUSIONS Results from this study suggest a pivot in how prognoses in DWM should be established and how parents should be counseled, along with a view of hydrocephalus and its treatment that challenges the current literature.

Evaluation of Prenatal Central Nervous System Anomalies: Obstetric Management, Fetal Outcomes and Chromosome Abnormalities

Objective: To study the prognostic outcomes of fetuses with prenatally diagnosed central nervous system (CNS) anomalies and describe the obstetric management for those fetuses.Methods: In this retrospective study, fetuses who were detected to have central nervous system by prenatal ultrasound from January 2010 to December 2019 were recruited. Data regarding prenatal diagnosis and obstetric outcome were retrieved from maternal and paediatric records. Prognosis of children who survived till delivery was classified based on their neurodevelopmental outcome within 2 years of life.Results: 365 fetuses were prenatally diagnosed with CNS malformations within the 10-year study period, at a mean gestational age of 24.65±7.37 weeks at diagnosis. Ventriculomegaly (23.36%) was the commonest CNS anomalies diagnosed antenatally. 198 (54.20%) fetuses has associated extra-CNS anomalies, with cardiovascular system being the most common organ system involved with CNS anomalies. Karyotyping was performed in 111 pregnancies, with chromosomal aberrations detected in 53 (49.07%) cases and culture failure in 3 cases. Edward syndrome and Patau syndrome were commonly associated with CNS anomalies. Fetuses with congenital CNS anomalies and abnormal chromosomal karyotyping more likely to be diagnosed earlier by prenatal ultrasound and tend to have poorer obstetric and neurocognitive prognosis. Among the 279 cases whom their pregnancy outcomes were available, 105 (37.63%) pregnancies were electively terminated, 35 (12.54%) pregnancies ended in spontaneous loss while the remaining 139 (49.82%) cases resulted in live births. The decision of TOP largely depends on mean diagnostic gestational age, presence of chromosomal aberrations and abnormal amniotic fluid volume in those fetuses. Ruling out 21 (15.11%) cases which were lost to 2-year follow-up, only 75 (53.96%) infants were still alive by the age of 2 years. Only 32 (23.02%) children with prenatally diagnosed CNS anomalies had normal neurodevelopmental outcome. The presence of multiple CNS anomalies and involvement of extra-CNS anomalies indicated a poorer neurodevelopmental prognosis.Conclusion: Less than 50% of fetuses with prenatally diagnosed CNS anomalies resulted in live births. Even if they survive till delivery, majority passed away within 2 years or had neurodevelopmental disability.

Detection rate of fetal CNS anomalies by first and second trimester ultrasound screening

Objectives: The aim of this study was to detect CNS abnormalities in the first and second trimester by ultrasound. Methods: This cross-sectional study was performed on pregnant women who referred to the radiology department of Imam Reza and Valiasr hospitals in Tehran-Iran during 2019-2020. After obtaining informed consent, pregnant women were screened in the first trimester at week 13-13 and then in the second trimester at week 18-20 by a 5-8 MHz Ultrasound Transducer. Each ultrasound included examination of the fetal brain and vertebrae at the axial coronal and sagittal planes in the most important anatomical areas, including the trans-thalamic (TT) or the trans-ventricular (TV) plane, transverse cerebellar, and vertebral canal plan. Ultrasound of the first and second trimesters of all mothers was performed. Information of all pregnant mothers was collected and recorded. Data analysis was performed using SPSS software version 25. Results: In this study, 2234 pregnant women were included in the study. The total rate of detected anomalies was found to be 1.3%. The rate of abnormalities detected in the first trimester was far less than in the second trimester. The prevalence of CNS anomalies in the population under 30 years of age was also found 0.9%, while it was 1.6% in the population over 30 years of age. Conclusion: Second-trimester ultrasound is the method of choice in diagnosing central nervous system abnormalities. However, first-trimester ultrasound is the diagnostic method for structural abnormalities of the skull.

Chromosomal Microarray Analysis in Pregnancies With Corpus Callosum or Posterior Fossa Anomalies

ObjectiveWe investigated the detection rate of clinically significant chromosomal microarray analysis (CMA) results in pregnancies with sonographic diagnosis of fetal corpus callosum anomalies (CCA) or posterior fossa anomalies (PFA).MethodsAll CMA tests in pregnancies with CCA or PFA performed between January 2015 and June 2020 were retrospectively evaluated from the Israeli Ministry of Health database. The rate of CMA with clinically significant (pathogenic or likely pathogenic) findings was calculated and compared to a local Israeli cohort of 5,541 pregnancies with normal ultrasound.ResultsOne hundred eighty-two pregnancies were enrolled: 102 cases with CCA and 89 with PFA (9 cases had both). Clinically significant CMA results were found in 7/102 of CCA (6.9%) and in 7/89 of PFA (7.9%) cases. The CMA detection rate in pregnancies with isolated CCA (2/57, 3.5%) or PFA (2/50, 4.0%) was lower than in nonisolated cases, including additional CNS and/or extra-CNS sonographic anomalies (CCA-5/45, 11.1%; PFA-5/39, 12.8%), but this was not statistically significant. However, the rate among pregnancies that had extra-CNS anomalies, with or without additional CNS involvement (CCA-5/24, 20.8%; PFA-5/29, 17.2%), was significantly higher compared to all other cases (p = 0.0075 for CCA; p = 0.035 for PFA). Risk of CMA with clinically significant results for all and nonisolated CCA or PFA pregnancies was higher compared to the background risk reported in the control cohort (p < 0.001), but was not significant for isolated cases.ConclusionsOur findings suggest that CMA testing is beneficial for the genetic workup of pregnancies with CCA or PFA, and is probably most informative when additional extra-CNS anomalies are observed.

Rhombencephalosynapsis, The Famous Unknown: Own Experience and Literature Review of Prenatal Diagnosis with Sonography and Magnetic Resonance Imaging

Rhombencephalosynapsis (RES) is a rare cerebellar malformation characterized by congenital fusion of the hemispheres and absence of the vermis. This condition is associated with developmental delay, seizures and involuntary head movements. Although the clinical and imaging aspect of this condition have been thoroughly investigated in the adult, prenatal diagnosis remains still a challenge in the modern Fetal-Maternal Medicine. Here we report our experience with 3 cases and review the current literature as well, focusing specifically on the obstetric imaging as well as on the prenatal diagnosis and management of this rare condition. RES should be considered in the differential diagnosis when absence of the vermis in the Posterior Fossa (PF) is suspected at prenatal Ultrasound Sonography (US), especially when ventriculomegaly or other Central Nervous System (CNS) anomalies are detected. A complete anatomical workup is necessary in these cases. Magnetic Resonance Imaging (MRI) remains to be the imaging modality of choice in confirming the diagnosis.

Fetal brain MRI: how it added to ultrasound diagnosis of fetal CNS anomalies-1 year experience

Background Central nervous system (CNS) anomalies are the most commonly diagnosed abnormalities of all fetal malformations and are usually primarily discovered on routine prenatal ultrasonography (US). Fetal magnetic resonance imaging (MRI) is a non-invasive technology with high soft tissue contrast that is documented to increase the diagnostic accuracy for detection of fetal brain anomalies. The aim of our study is to analyze the value of adding magnetic resonance imaging (MRI) of the fetal brain to antenatal ultrasound in the diagnosis of fetal central nervous system (CNS) anomalies. Results We diagnosed various CNS anomalies including twelve cases with infra- and supra-tentorial arachnoid cysts, six cases had Dandy-Walker malformation (DWM) and its variants, 1 case with mega cisterna magna, 2 cases of holoprosencephaly, 1 case of hydranencephaly, 2 cases with supratentorial hydrocephalus, 1 case of craniopharyngioma, 6 cases with corpus callosum (CC) agenesis, 1 case of extradural hematoma, and 8 cases with Meckel-Gruber syndrome (MGS). MRI diagnosis confirmed the ultrasound finding, without additional information in 23 cases (57.5%%), added an extra finding in 11 cases (27.5%), differentiated between 2 pathologies in 3 cases (7.5%), and changed the diagnosis in 3 cases (7.5 %). The 40 pregnancies resulted in 27 births (67.5%), 2 died directly after birth (5%), 7 terminations (17.5%), and 4 intrauterine fetal deaths (IUFD) (10 %). Conclusion Ultrasound is the gold standard imaging modality for anomaly scan in the second and third trimesters; however, MRI of the fetal brain might be a clinically valuable complement especially when ultrasound examination is inconclusive due to maternal obesity, severe oligohydramnios, or in complicated cases with unclear diagnosis.

Detection of copy number variation associated with ventriculomegaly in fetuses using single nucleotide polymorphism arrays

Etiopathogenesis of fetal ventriculomegaly is poorly understood. Associations between fetal isolated ventriculomegaly and copy number variations (CNVs) have been previously described. We investigated the correlations between fetal ventriculomegaly—with or without other ultrasound anomalies—and chromosome abnormalities. 222 fetuses were divided into four groups: (I) 103 (46.4%) cases with isolated ventriculomegaly, (II) 41 (18.5%) cases accompanied by soft markers, (III) 33 (14.9%) cases complicated with central nervous system (CNS) anomalies, and (IV) 45 (20.3%) cases with accompanying anomalies. Karyotyping and single nucleotide polymorphism (SNP) array were used in parallel. Karyotype abnormalities were identified in 15/222 (6.8%) cases. Karyotype abnormalities in group I, II, III, and IV were 4/103 (3.9%), 2/41 (4.9%), 4/33 (12.1%), and 5/45 (11.1%), respectively. Concerning the SNP array analysis results, 31/222 (14.0%) were CNVs, CNVs in groups I, II, III, and IV were 11/103 (10.7%), 6/41 (14.6%), 9/33 (27.3%), and 5/45 fetuses (11.1%), respectively. Detections of clinical significant CNVs were higher in non-isolated ventriculomegaly than in isolated ventriculomegaly (16.81% vs 10.7%, P = 0.19). SNP arrays can effectively identify CNVs in fetuses with ventriculomegaly and increase the abnormal chromosomal detection rate by approximately 7.2%, especially ventriculomegaly accompanied by CNS anomalies.

The Spectrum of Congenital Central Nervous System Anomalies Among Stillborn: An Autopsy Based Study

Background: Congenital central nervous system (CNS) anomalies are the structural or functional abnormalities of the brain and spinal cord that occur during the intrauterine developmental process. Purpose: The present study aims to detect the prevalence of congenital CNS anomalies among stillborn fetuses, the association between congenital anomalies and maternal factors, and also the association between autopsy and ultrasound findings. Methods: This study was conducted on 50 stillborn fetuses, obtained from the Department of Obstetrics and Gynecology at JSS Medical College and Hospital, Mysuru. The fetuses were fixed in 10% formalin and autopsies were performed as per the standard fetal autopsy protocol. The congenital CNS anomalies were studied in detail. Results: CNS anomalies were the most common congenital anomalies observed. Out of the total 50 stillborn fetuses studied, CNS anomalies were found in 17 fetuses and their occurrence was more common among male stillborn than females. Meningomyelocele was the most common anomaly, followed by anencephaly. The other anomalies documented were meningocele, encephalocele, meningoencephalocele, agenesis of the corpus callosum, craniorachischisis, bifid cerebellum with hypoplastic vermis, holoprosencephaly, and sirenomelia. Fisher’s exact test showed a significant association between maternal hypothyroidism and congenital CNS anomalies ( P < .05). The autopsy confirmed the ultrasound findings in 40 (80%) fetuses. There were significant additional findings observed in seven (14%) fetal autopsies and ultrasound diagnosis completely changed in three (6%) cases, after the final autopsy procedure. Conclusion: The fetal autopsy is the single most directly evident investigation, which gives information that changes or significantly improves the clinical diagnosis. A multidisciplinary holistic approach toward pregnancy will help to detect any kind of abnormality in the fetus and thus to take a timely decision toward the management.