Systematic analysis of genotype-phenotype variability in siblings with Aicardi Goutières Syndrome (AGS).

OBJECTIVE: Aicardi Goutières Syndrome (AGS) is a genetic interferonopathy associated with multisystemic heterogeneous disease and neurologic dysfunction. AGS includes a broad phenotypic spectrum which is only partially explained by genotype. To better characterize this variability, we will perform a systematic analysis of phenotypic variability in familial cases of AGS. METHODS: Among thirteen families, twenty-six siblings diagnosed with AGS were identified from the Myelin Disorders and Biorepository Project (MDBP) at the Children's Hospital of Philadelphia. Data were collected on the age of onset, genotype, neurologic impairment, and systemic complications. Neurologic impairment was assessed by a disease-specific scale (AGS Severity Scale) at the last available clinical encounter (range: 0-11 representing severe - attenuated phenotypes). The concordance of clinical severity within sibling pairs was categorized based on the difference in AGS Scale (discordant defined as >2-unit difference). The severity classifications were compared between sibling sets and by genotype. RESULTS: Five genotypes were represented: TREX1 (n = 4 subjects), RNASEH2B (n = 8), SAMHD1 (n = 8) ADAR1 (n = 4), and IFIH1 (n = 2). The older sibling was diagnosed later relative to the younger affected sibling (median age 7.32 years [IQR = 14.1] compared to 1.54 years [IQR = 10.3]). Common presenting neurologic symptoms were tone abnormalities (n = 10/26) and gross motor dysfunction (n = 9/26). Common early systemic complications included dysphagia and chilblains. The overall cohort median AGS severity score at the last encounter was 8, while subjects presenting with symptoms before one year had a median score of 5. The TREX1 cohort presented at the youngest age and with the most severe phenotype on average. AGS scores were discordant for 5 of 13 sibling pairs, most commonly in the SAMHD1 pairs. Microcephaly, feeding tube placement, seizures and earlier onset sibling were associated with lower AGS scores (respectively, Wilcoxon rank sum: p = 0.0001, p < 0.0001, p = 0.0426, and Wilcoxon signed rank: p = 0.0239). CONCLUSIONS: In this systematic analysis of phenotypic variability in familial cases, we found discordance between siblings affected by AGS. Our results underscore the heterogeneity of AGS and suggest factors beyond AGS genotype may affect phenotype. Understanding the critical variables associated with disease onset and severity can guide future therapeutic interventions and clinical monitoring. This report reinforces the need for further studies to uncover potential factors to better understand this phenotypic variability, and consequently identify potential targets for interventions in attempt to change the natural history of the disease.

A 13-Year-Old Girl with Caudal Regression Syndrome and Distal Vaginal Atresia: A Case Report.

BACKGROUND Caudal regression syndrome (CRS) is a rare anomaly characterized by maldevelopment of the caudal half of the body and can involve the genitourinary system. This report presents the case of a 13-year-old girl diagnosed with CRS and previously unknown distal vaginal atresia, presenting with monthly pelvic pain. CASE REPORT A 13-year-old pre-menarcheal patient with CRS sought emergency care due to debilitating monthly pelvic pain persisting for 3 months. Pelvic examination revealed the absence of a vaginal opening, and a rectal exam showed a 5-cm large bulge anteriorly, along with a 2-cm fibrous septum in the distal portion of the vagina. Pelvic ultrasound and magnetic resonance imaging confirmed the presence of hematometrocolpus and hematosalpinx on the right adnexa, while the left ovary was not identified. Treatment commenced with fixed analgesia and combined continuous oral contraception. Due to the persistent pain and uncertainty regarding the anatomy of the internal reproductive organs, diagnostic laparoscopy with drainage of the hematocolpus was performed 2 weeks later. Six months later, after multidisciplinary discussion, definitive surgery (pull-through vaginoplasty) was carried out, allowing for emotional preparation for postoperative dilation. One year after the definitive surgery, the patient remains asymptomatic, experiencing regular withdrawal bleeding with no signs of obstruction. CONCLUSIONS Patients with musculoskeletal anomalies should undergo urogenital tract evaluation. Timely identification of distal vaginal atresia is pivotal for devising appropriate treatment and averting complications. During the acute phase, laparoscopic drainage can alleviate symptoms and clarify anatomy, without compromising the success of subsequent definitive surgery.

Exome sequencing identifies homozygous variants in MBOAT7 associated with neurodevelopmental disorder.

Intellectual disability (ID) is a large group of neurodevelopmental disorders characterized by a congenital limitation in intellectual functioning (reasoning, learning, and problem solving), adaptive behavior (conceptual, social, and practical skills), originated at birth and manifested before the age of 18. By whole exome sequencing of five consanguineous Pakistani families presenting hallmark features of ID, global developmental delay, aggressive and self-injurious behaviors, microcephaly, febrile seizures and facial dysmorphic features, we identified three novel homozygous missense variants (NM_024298.5: c.588G > T; p.Trp196Cys, c.736 T > C; p.Tyr246His and c.524A > C; p. Asp175Ala) and one rare homozygous in-frame deletion variant (c.758_778del;p.Glu253_Ala259del) in membrane-bound O-acyltransferase family member 7 (MBOAT7) gene previously associated with autosomal recessive neurodevelopmental disorder. The segregation of the variants was validated by Sanger sequencing in all family members. In silico homology modeling of wild-type and mutated proteins revealed substantial changes in the structure of both proteins, indicating a possible effect on function. The identification and validation of new pathogenic MBOAT7 variants in five cases of autosomal recessive ID further highlight the importance of this genes in proper brain function and development.

Surgical treatment of interhemispheric arachnoid cysts.

OBJECTIVE: In children, interhemispheric arachnoid cysts (IHACs) are rare lesions often associated with corpus callosum dysgenesis. It is still controversial about surgical treatments for IHACs. We aim to report our experience with pediatric IHAC patients and evaluate surgical courses and neurological developments. METHODS: Pediatric IHACs treated between 2001 and 2021 were reviewed retrospectively. IHAC was observed until they represented rapid cyst enlargement or neurological symptoms. Cyst fenestration was done by microscope or endoscope, depending on the IHAC's location. Cyst size and corpus callosum dysgenesis were evaluated with neuroimaging. Neurological development was assessed from medical records at the last follow-up. RESULTS: Fifteen children received cyst fenestration surgery (mean age 11.4 months). Eleven patients (73.3%) under observation showed rapid cyst enlargement in a short period (median 5 months). Cysto-ventriculostomy (CVS) and cysto-cisternostomy (CCS) regressed the cyst size significantly (p = 0.003). The median follow-up duration was 51 months (range 14-178 months). Corpus callosum dysgenesis was observed in eleven patients (73.3%, complete = 5, partial = 6). Among eight patients (53.3%) having developmental delay, five patients (33.3%) showed speech delay, including one patient with intractable seizures. CONCLUSION: Pediatric IHACs frequently present within 1 year after birth, with rapid cyst enlargement. CVS and CCS were effective in regressing the cyst size. Corpus callosum dysgenesis accompanied by IHAC might have a risk of language achievement; however, development delay could rely on multifactorial features, such as epilepsy or other brain anomalies.

Clinical phenotype and genetic characteristics of SZT2 related diseases: A case report and literature review.

PURPOSE: Seizure threshold 2 protein homolog gene (SZT2, MIM: 615463) related diseases are extremely rare autosomal recessive disorders with a wide spectrum of clinical phenotypes ranging from mild intellectual impairment to severe developmental epileptic encephalopathy (DEE). Most SZT2 related diseases are accompanied by craniofacial malformation and corpus callosum malformation. This study attempts to analyze and summarize the clinical phenotype and genetic characteristics of SZT2 related diseases, providing a basis for early diagnosis, treatment, and prognosis. METHOD: We analyzed the clinical characteristics of a Chinese child with pathogenic variants of SZT2. We also performed whole-exome sequencing (WES) on the patient. In addition, we conducted a literature review of previously reported patients with pathogenic mutations in the SZT2 gene. RESULT: The proband was a boy aged 1 year and 9 months with severe global developmental delay, transient drug-controlled focal epilepsy, cluster epilepsy, autism spectrum disorder, craniofacial deformity, hypotonia, focal EEG discharge, corpus callosum malformation, and persistent cavum septum pellucidum. WES revealed that the patient carried the SZT2 gene c.7584dupA and c.6302A>C complex heterozygous variants; the former being Likely Pathogenic (LP) and the latter Uncertain Significance (VUS) according to ACMG classification guidelines. According to our literature review, 43 cases of SZT2 related diseases have been reported so far; these include 15 cases with homozygous variations and 28 cases with complex heterozygous variations. A total of 57 types of variation were found, including 47 genetic variants, 2 de novo variants, and 8 unknown genetic modes. In addition, 2 high-frequency variants were found (c.5949_5951delTGT and c.6553C>T). The main clinical manifestations of the 40 patients were global developmental delay (GDD) of varying degrees (38/40, 95.00 %), seizures (36/40, 90.00 %), cranial deformity (27/40, 67.50 %), facial deformity (22/40, 55.00 %), hypotonia (22/40, 55.00 %), abnormal interseizure EEG discharge (26/40, 65.00 %), slow background activity (20/40, 50.00 %), corpus callosum deformity (18/40, 45.00 %). There was also one case of sudden unexpected death in epilepsy (SUDEP) and 3 cases of death from infection. In addition, three fetuses with the same variant had hydrocephalus and encephalocele. CONCLUSION: The compound heterozygous mutation of c.7584dupA and c.6302A>C in the SZT2 gene is the genetic etiology of this patient, expanding the mutation spectrum of SZT2 related diseases. Early genetic testing is the best choice for clear diagnosis, treatment, and prognosis.

Prenatal diagnosis of microcephaly through combined MRI and ultrasonography: Analysis of a case series.

INTRODUCTION: Intrauterine microcephaly is a complex and lifelong condition that poses significant ethical challenges for clinicians and parents. The prognosis of microcephaly is highly variable and depends on the underlying cause and severity. In addition, microcephaly is often associated with various comorbidities, including intellectual disability, developmental delay, and epilepsy. Ultrasonography (US) is currently the most commonly used imaging modality for detecting microcephaly in the second trimester of pregnancy. However, antenatal brain magnetic resonance imaging (MRI) is increasingly being used as a more sensitive tool to identify structural abnormalities that may suggest a specific diagnosis. In this study, we report a case series of microcephaly diagnosed through the combination of MRI and US. PATIENT CONCERNS: How to utilize a combination of MRI and US to screen for fetal microcephaly. DIAGNOSIS: Based on the results of US and MRI examinations, patient 1 was found to have other craniocerebral malformations, patient 2 demonstrated macrogyria, and patient 3 exhibited skull irregularities. INTERVENTIONS: The pregnancies of all 3 patients were terminated through the induction of labor by injecting Rivanol into the amniotic cavity. OUTCOMES: The 3 patients were discharged after a period of observation. CONCLUSION: US is an important tool for diagnosing fetal microcephaly. However, MRI can overcome the limitations of US and detect additional brain structural abnormalities, thereby providing more specific and valuable prenatal diagnostic information. Therefore, combining MRI and US has significant diagnostic value for fetal microcephaly.

Treatment Effect on Brain Atrophy Correlates with Treatment Effect on Cognition in Multiple Sclerosis.

OBJECTIVE: The purpose of this study was to evaluate the extent to which treatment effect on magnetic resonance imaging (MRI)-derived measures of brain atrophy and focal lesions can mediate, at the trial level, the treatment effect on cognitive outcomes in multiple sclerosis (MS). METHODS: We collected all published randomized clinical trials in MS lasting at least 2 years and including as end points: active MRI lesions (defined as new/enlarging T2 lesions), brain atrophy (defined as a change in brain volume between month 12 and month 24), and change in cognitive performance (assessed by the Paced Auditory Serial Addition Test [PASAT]). Relative reductions were used to quantify the treatment effect on MRI markers (lesions and atrophy), whereas the standardized mean difference (Hedges g) between baseline and follow-up cognitive assessment was used to quantify the treatment effects on cognition. A linear regression, weighted for trial size, was used to assess the relationship between the treatment effects on MRI markers and cognition. RESULTS: Fourteen trials including more than 8,813 patients with MS were included in the meta-regression. Treatment effect on cognition was strongly associated with the treatment effect on brain atrophy (R2 = 0.79, p < 0.001), but was not correlated with the treatment effect on active MRI lesions (R2 = 0.16, p = 0.14). INTERPRETATION: Results reported here suggest that brain atrophy, a well-established MRI marker in MS clinical trials, can be used as a main outcome for clinical trials with drugs targeting cognitive impairment and neurodegeneration. ANN NEUROL 2023;94:925-932.

Longitudinal evolution of central nervous system anomalies in fetuses with open spina bifida fetoscopic repair and correlation with neurologic outcome.

BACKGROUND: Open spina bifida is associated with central nervous system anomalies such as abnormal corpus callosum and heterotopias. However, the impact of prenatal surgery over these structures remains unclear. OBJECTIVE: This study aimed to describe longitudinal changes of central nervous system anomalies before and after prenatal open spina bifida repair and to evaluate their relationship with postnatal neurologic outcomes. STUDY DESIGN: Retrospective cohort study of fetuses with open spina bifida who underwent percutaneous fetoscopic repair from January 2009 to August 2020. All women had presurgical and postsurgical fetal magnetic resonance imaging, at an average of 1 week before and 4 weeks after surgery, respectively. We evaluated defect characteristics in the presurgical magnetic resonance images; and fetal head biometry, clivus supraocciput angle, and the presence of structural central nervous system anomalies, such as abnormalities in corpus callosum, heterotopias, ventriculomegaly, and hindbrain herniation, in both presurgical and postsurgical magnetic resonance images. Neurologic assessment was performed using the Pediatric Evaluation of Disability Inventory scale in children who were 12 months or older, covering 3 different sections, namely self-care, mobility, and social and cognitive function. RESULTS: A total of 46 fetuses were evaluated. Presurgery and postsurgery magnetic resonance imaging were performed at a median gestational age of 25.3 and 30.6 weeks, with a median interval of 0.8 weeks before surgery, and 4.0 weeks after surgery. There was a 70% reduction in hindbrain herniation (100% vs 32.6%; P<.001), and a normalization of the clivus supraocciput angle after surgery (55.3 [48.8-61.0] vs 79.9 [75.2-85.4]; P<.001). No significant increase in abnormal corpus callosum (50.0% vs 58.7%; P=.157) or heterotopia (10.8% vs 13.0%; P=.706) was observed. Ventricular dilation was higher after surgery (15.6 [12.7-18.1] vs 18.8 [13.7-22.9] mm; P<.001), with a higher proportion of severe ventricular dilation after surgery (≥15mm) (52.2% vs 67.4%; P=.020). Thirty-four children underwent neurologic assessment, with 50% presenting a global optimal Pediatric Evaluation of Disability Inventory result and 100% presenting a normal social and cognitive function. Children with optimal global Pediatric Evaluation of Disability Inventory presented a lower rate of presurgical anomalies in corpus callosum and severe ventriculomegaly. When analyzed as independent variables to global Pediatric Evaluation of Disability Inventory scale, the presence of abnormal corpus callosum and severe ventriculomegaly showed an odds ratio of 27.7 (P=.025; 95% confidence interval, 1.53-500.71) for a suboptimal result. CONCLUSION: Prenatal open spina bifida repair did not change the proportion of abnormal corpus callosum nor heterotopias after surgery. The combination of presurgical abnormal corpus callosum and severe ventricular dilation (≥15 mm) is associated with an increased risk of suboptimal neurodevelopment.

Angioarchitecture and genetic variants of spinal cord cavernous malformations and associated developmental venous anomalies: a case report.

Cavernous malformations (CM) have long been considered congenital of central nervous system, while the mechanism of CMs detailed development process associated with genetic factors remains unclear. We reported an uncommon case which suffered spinal cord cavernous malformations. In this work, representative samples were obtained, and the sequenced results were described for the first time. A 9-year-old boy was found oblique shoulder with slightly weakness of left limbs; MRI indicated spinal cord cavernous malformations (CMs) located at the C4-C6 vertebral level. On genetic analysis, a shared mutation of PIK3CA (p.H1047R) in CMs and associated developmental venous anomalies (DVAs) was detected, with a different abundance (2% and 7%, respectively), and a somatic mutation of MAP3K3 (p.I441M) was detected in the CM tissue samples. This case provides better knowledge of the formation history and genetic triggers of the DVA-associated CMs. This evidence allows us to speculate the developmental history of the CM lesion: The DVA with PIK3CA mutation might be genetic precursor, and then the associated CM could be derived from terminal cell population of the DVA by acquiring a somatic mutation in MAP3K3.

Case report: double dermal sinus tracts of the cervical and thoracic spine associated with congenital intracranial pathology (hydrocephalus and an interhemispheric cyst) in a newborn patient.

INTRODUCTION: A dermal sinus tract (DST) is an uncommon type of spinal dysraphisms characterized by a tract lined with stratified squamous epithelium that extends from the subcutaneous tissue to the underlying thecal sac or neural tube. These developmental anomalies can present asymptomatically with cutaneous abnormalities or with devastating complications. Usually, it is presented as a unique lesion, and there are only a few reports that show multiple sinuses, and none of them associated with midline brain malformations. METHODS: We present the case of a 3-day-old girl with an antenatal diagnosis of hydrocephalus who was diagnosed with double dermal sinus tracts of the cervical and thoracic regions at admission. The patient presented signs of elevated intracranial pressure (ICP), which imposed a challenge in the management of the case. RESULTS: Our patient was successfully treated initially with a lumbar puncture in order to discard a cerebrospinal fluid (CSF) infection. With negative CSF cultures, a ventriculoperitoneal shunt (VPS) was placed. Nine days after the VPS surgery and without signs of infection, the DST was excised in a single procedure, without follow-up complications. CONCLUSION: To our knowledge, this is the first description of a patient with multiple midline neural tube defects (NTDs) associated with congenital intracranial pathology. Although there are no guidelines regarding the best treatment for this complex associated pathology, the patient was treated, without follow-up complications.

Characteristics associated with drug resistant epilepsy in children up to 36 months old with Congenital Zika Syndrome.

OBJECTIVES: To verify characteristics associated with drug resistant epilepsy in children up to 36 months of age with Congenital Zika Syndrome (CZS). METHODS: This is a prospective cohort study with children aged up to 36 months diagnosed with CZS. Obstetric, demographic, phenotype and other clinical signs, cranial tomography, growth and motor development of the children were collected. RESULTS: Of a total of 109 children diagnosed with CZS, 100 (91.7%) had epilepsy and 68 (68%) with drug resistant seizures. The types of seizures associated with drug resistant epilepsy were focal seizures from the occipital lobe, generalized tonic and generalized tonic-clonic seizures. There was an association between drug resistant epilepsy and microcephaly at birth, severe microcephaly at birth, excess nuchal skin, ventriculomegaly, reduced brain parenchyma volume, and hypoplasia or malformation of the cerebellum. Difficulty sleeping, irritability, continuous crying, dysphagia and gross motor function were clinical signs associated with drug resistant epilepsy, as were the presence of ocular abnormalities, low head circumference in the first year of life and low weight in the first six months. CONCLUSIONS: The prevalence of drug resistant epilepsy in children up to 36 months with CZS was 62.4% and was associated with the severity of the child's neurological damage, with emphasis on the reduction of brain parenchyma volume and damage to the cerebellum.

Fetal cerebral ventriculomegaly: What do we tell the prospective parents?

Fetal cerebral ventriculomegaly is a relatively common finding, observed during approximately 1% of obstetric ultrasounds. In the second and third trimester, mild (≥10 mm) and severe ventriculomegaly (≥15 mm) are defined according to the measurement of distal lateral ventricles that is included in the routine sonographic examination of central nervous system. A detailed neurosonography and anatomy ultrasound should be performed to detect other associated anomalies in the central nervous system and in other systems, respectively. Fetal MRI might be useful when neurosonography is unavailable or suboptimal. The risk of chromosomal and non-chromosomal genetic disorders associated with ventriculomegaly is high, therefore invasive genetic testing, including microarray, is recommended. Screening for prenatal infections, in particular cytomegalovirus and toxoplasmosis, should also be carried out at diagnosis. The prognosis is determined by the severity of ventriculomegaly and/or by the presence of co-existing abnormalities. Fetal ventriculoamniotic shunting in progressive isolated severe ventriculomegaly is an experimental procedure. After delivery, ventricular-peritoneal shunting or ventriculostomy are the two available options to treat hydrocephalus in specific conditions with similar long-term outcomes. A multidisciplinary fetal neurology team, including perinatologists, geneticists, pediatric neurologists, neuroradiologists and neurosurgeons, can provide parents with the most thorough prenatal counseling. This review outlines the latest evidence on diagnosis and management of pregnancies complicated by fetal cerebral ventriculomegaly.

Changes of Atherosclerotic Plaque in Cerebral Artery Stenosis According to High-Resolution MR Imaging.

Atherosclerosis can affect multiple arteries, and result in stroke and heart disease. Clinical and conventional imaging is insufficient to predict the progression of atherosclerosis. This study investigates risk factors that rely on high-resolution magnetic resonance imaging (HR-MRI). Patients with cerebral artery stenosis who had undergone HR-MRI at least twice were included. The demographics, risk factors, and proportion of patients with cerebral artery stenosis were investigated. The association between atherosclerotic plaque characteristics and the progression or regression of artery stenosis was also analyzed. A total of 42 patients were analyzed, with a median follow-up of 16.88 ± 12.53 months. The mean age of all subjects was 63.1 ± 9.15 years, and 83.3% of them were male. The incidences of stenosis of the basilar, proximal internal carotid, and middle cerebral arteries were 21.4%, 61.9%, and 16.7%, respectively. Intraplaque hemorrhage (IPH) was detected in 20 (47.6%) patients. Multivariate analysis showed that age (odds ratio (OR), 0.87; p = 0.014), smoking (OR, 0.11; p = 0.033), and IPH regression (OR, 10.13; p = 0.027) were associated with stenosis regression. The progression of IPH (OR, 115.80; p = 0.007) was associated with stenosis progression. Results suggest that IPH on HR-MRI is associated with changes in cerebral atherosclerotic stenosis.

Child Neurology: Aicardi-Goutières Syndrome Presenting as Recurrent Ischemic Stroke.

Aicardi-Goutières syndrome (AGS) is a rare, single-gene disorder, characterized by neurologic and skin involvement with an increased level of interferon-α (IFN-α) in the CSF. We describe the case of a young patient presenting with recurrent ischemic stroke. Evaluation revealed the presence of chilblains, white matter abnormalities, cerebral atrophy, and raised IFN-α in the CSF. Compound heterozygous variants of TREX1 were detected, confirming a diagnosis of AGS. After excluding other causes, we attributed the stroke to AGS. Tofacitinib, a Janus kinase inhibitor, was administered to our patient in addition to antiplatelet drugs. There was no recurrence of stroke during 3-month follow-up. This is a rare case of recurrent stroke in TREX1-mutated AGS. Small vessel involvement has been previously demonstrated to play a significant role in the pathogenesis of AGS. This microvascular mechanism might explain the occurrence of ischemic stroke in our patient. For young patients with stroke and multiple system involvement, genetic disorders including AGS should be considered.

Critical Appraisal of Randomized Controlled Trials on Unruptured Brain Arteriovenous Malformations.

OBJECTIVE: Brain arteriovenous malformations management remains controversial despite the numerous, available treatment options. Randomized controlled trials (RCTs) theoretically provide the strongest evidence for the assessment of any therapeutic intervention. However, poorly designed RCTs may be associated with biases, inaccuracies, and misleading conclusions. The purpose of our study is to assess reporting transparency and methodological quality of the existing RCTs. METHODS: A search was performed in the PubMed, Scopus, Embase, clinicaltrials.gov, and Cochrane databases. The search was limited to English literature. We included all published RCTs reporting on the management of unruptured brain arteriovenous malformations. The eligible studies were evaluated by 5 blinded raters with the CONsolidated Standards of Reporting Trials 2010 statement and the risk-of-bias 2 tool. The inter-rater agreement was assessed with the Fleiss' Kappa. RESULTS: A randomized trial of unruptured brain arteriovenous malformations (ARUBA) and treatment of brain arteriovenous malformations (TOBAS) trials were evaluated. ARUBA achieved high CONsolidated standards of reporting trials compliance, while TOBAS showed a moderate one. In ARUBA the introduction, discussion, and other information sections reached the highest compliance rate (80%-86%). The lowest rates were recorded in the results and the methods (62% and 73%, respectively). The inter-rater agreement was moderate to substantial (54.1% to 78.4%). All the examined studies demonstrated a high risk of bias, mainly related to ill-defined intended interventions, missing outcome data, and selection of the reported results. CONCLUSIONS: Our study confirmed the high risk of bias mainly attributed to several protocol violations, deviations, minimal external validity and selection, attrition, and allocation biases of the ARUBA trial. Analysis of the TOBAS trial revealed a moderate overall reporting clarity and a high risk of bias.

Genetics and Emerging Therapies for Brain Arteriovenous Malformations.

Brain arteriovenous malformations (AVMs) are characterized by a high-pressure, low-resistance vascular nidus created by direct shunting of blood from feeding arteries into arterialized veins, bypassing intervening capillaries. AVMs pose a risk of spontaneous rupture because the vessel walls are continuously exposed to increased shear stress and abnormal flow phenomena, which lead to vessel wall inflammation and distinct morphologic changes. The annual rupture rate is estimated at 2%, and once an AVM ruptures, the risk of rerupture increases 5-fold. The ability of AVMs to grow, regress, recur, and undergo remodeling shows their dynamic nature. Identifying the underlying cellular and molecular pathways of AVMs not only helps us understand their natural physiology but also allows us to directly block vital pathways, thus preventing AVM development and progression. Management of AVMs is challenging and often necessitates a multidisciplinary approach, including neurosurgical, endovascular, and radiosurgical expertise. Because many of these procedures are invasive, carry a risk of inciting hemorrhage, or are controversial, the demand for pharmacologic treatment options is increasing. In this review, we introduce novel findings of cellular and molecular AVM physiology and highlight key signaling mediators that are potential targets for AVM treatment. Furthermore, we give an overview of syndromes associated with hereditary and nonhereditary AVM formation and discuss causative genetic alterations.

Protocol for in utero injection to investigate Zika virus-related fetal microcephaly in mice.

Zika virus (ZIKV) is linked to congenital defects including microcephaly. An infection model that can recapitulate most microcephaly-related phenotypes is crucial for understanding ZIKV pathogenesis. Here, we present a protocol to generate ZIKV from an infectious clone through a reverse genetic system and subsequently perform embryonic brain infection with the rescued ZIKV in pregnant mice. We optimized several aspects of the procedures including virus rescue and in utero injection. This protocol facilitates reproducible investigation of virus-induced cortical development defects. For complete details on the use and execution of this protocol, please refer to Zeng et al. (2020).

Prenatal intracranial hypotension syndrome: new insights into the mechanisms of fenestration of septi pellucidi and ventriculomegaly in fetuses with open spinal dysraphism.

OBJECTIVE: To study the prevalence of abnormalities of the septi pellucidi (SP) in a cohort of fetuses with open spinal dysraphism (OSD) and to determine whether this condition is secondary to obstructive ventriculomegaly and, therefore, part of the natural history of prenatal intracranial hypotension (PICH) syndrome. METHODS: Magnetic resonance imaging (MRI) studies from fetuses with OSD were analyzed. The SP were assessed using axial and coronal T2-weighted images of the fetal brain and classified as intact, partially absent, or completely absent. Additionally, the correlation between the presence or absence of the SP and the size of the lateral ventricles, degree of cerebellar tonsillar herniation, collapse of the fourth ventricle, and interpeduncular angle was investigated. RESULTS: A total of 32 fetuses with OSD were studied. Mean gestational age at the time of the fetal MRI was 25.5 ± 3.9 weeks (range, 19-35) and mean ventricular size was 16.2 ± 4.2 mm (range, 8-26). Twenty-three (71.9%) fetuses had cerebellar tonsillar herniation. The IPA was completely collapsed in 23 cases (71.9%), reduced in seven (21.9%), and unreadable in two (6.3%). Twenty (62.5%) fetuses presented with intact SP, 10 (31.3%) with partially absent SP (incomplete fenestration), and two (6.3%) with completely absent SP (complete fenestration). Fenestration of the SP correlated significantly with the degree of ventriculomegaly (Pearson's correlation coefficient =0.459; p = .01). However, there was no correlation with the IPA, collapse of the fourth ventricle, and cerebellar tonsillar herniation. CONCLUSIONS: More than one-third of the fetuses with OSD had fenestration of the SP. The most probable etiology is increased intraventricular pressure leading to local necrosis of the SP. As fenestration of the SP is a secondary event associated with PICH syndrome, this condition should not be considered a contraindication for intrauterine repair of the spinal defect. Instead, it should be seen as an indicator of the severity of the intraventricular pressure.