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The Hindbrain Choroid Plexus is a complex, cerebrospinal fluid-secreting tissue that projects into the 4th vertebrate brain ventricle. Despite its irreplaceability in the development and homeostasis of the entire central nervous system, the research of Hindbrain Choroid Plexus and other Choroid Plexuses has been neglected by neuroscientists for decades. One of the obstacles is the lack of tools that describe the complex shape of the Hindbrain Choroid Plexus in the context of brain ventricles. Here we introduce an effective tool, termed Ch O P-CT, for the noninvasive, X-ray micro-computed tomography-based, three-dimensional visualization and subsequent quantitative spatial morphological analysis of developing mouse Hindbrain Choroid Plexus. Ch O P-CT can reliably quantify Hindbrain Choroid Plexus volume, surface area, length, outgrowth angle, the proportion of the ventricular space occupied, asymmetries and general shape alterations in mouse embryos from embryonic day 13.5 onwards. We provide evidence that Ch O P-CT is suitable for the unbiased evaluation and detection of the Hindbrain Choroid Plexus alterations within various mutant embryos. We believe, that thanks to its versatility, quantitative nature and the possibility of automation, Ch O P-CT will facilitate the analysis of the Hindbrain Choroid Plexus in the mouse models. This will ultimately accelerate the screening of the candidate genes and mechanisms involved in the onset of various Hindbrain Choroid Plexus-related diseases., (© 2024. The Author(s).)

West Nile Virus (WNV) belongs to the Flaviviridae family of viruses. It was first isolated and identified in 1937. Patients typically present with flu-like symptoms or are asymptomatic; however, neuroinvasive West Nile can lead to significant neurological impairment. Herein presented is a catastrophic case of WNV rhombencephalitis in a male patient newly diagnosed with AIDS. This report sheds light on the potential for severe neurological complications in co-infected patients and emphasizes the importance of early recognition., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: To date, few studies have explored the specific risk factors of patients with listeriosis who develop rhombencephalitis, and there is insufficient information regarding imaging findings and clinical symptoms in patients with this disease. This work aimed to analyze the imaging findings associated with L. monocytogenes rhombencephalitis in a cohort of patients with listeriosis., Materials and Methods: We conducted a retrospective observational study of all declared cases of listeriosis in a tertiary hospital from Granada, Spain, from 2008 to 2021. Risk factors, comorbidities, and clinical outcomes were collected for all patients. In addition, clinical symptoms and magnetic resonance imaging (MRI) findings were included for those patients who developed rhombencephalitis. Descriptive and bivariate analyses were performed using SPSS statistical software (IBM SPSS, version 21)., Results: Our cohort comprised 120 patients with listeriosis (41.7% women, mean age: 58.6 ± 23.8 years), of which 10 (8.3%) had rhombencephalitis. The most frequent MRI findings in patients with confirmed rhombencephalitis were T2-FLAIR hyperintensity (100%), T1 hypointensity (80%), scattered parenchymal enhancement (80%), and cranial nerve enhancement (70%), while the most frequent anatomical involvement were pons, medulla oblongata, and cerebellum. Complications occurred in 6 patients (abscess in 4, hemorrhage in 2, hydrocephalus in 1)., Conclusions: Rhombencephalitis is associated with an increased in-hospital mortality in patients with listeriosis. The anatomical distribution and imaging characteristics of neurolisteriosis could be useful to suggest the diagnosis. Future studies with greater sample size should explore the association between anatomical location, imaging patterns, and associated complications (e.g., hydrocephalus, hemorrhage), and clinical outcomes.

Objective: The aim of this study was to determine whether reversal of hindbrain herniation (HBH) on MRI following prenatal repair of neural tube defects (NTDs) is associated with reduced rates of ventriculoperitoneal (VP) shunt placement or endoscopic third ventriculostomy (ETV) within the 1st year of life., Methods: This is a secondary analysis of prospectively collected data from all patients who had prenatal open repair of a fetal NTD at a single tertiary care center between 2012 and 2020. Patients were offered surgery according to inclusion criteria from the Management of Myelomeningocele Study (MOMS). Patients were excluded if they were lost to follow-up, did not undergo postnatal MRI, or underwent postnatal MRI without a report assessing hindbrain status. Patients with HBH reversal were compared with those without HBH reversal. The primary outcome assessed was surgical CSF diversion (i.e., VP shunt or ETV) within the first 12 months of life. Secondary outcomes included CSF leakage, repair dehiscence, CSF diversion prior to discharge from the neonatal intensive care unit (NICU), and composite neonatal morbidity. Demographic, prenatal sonographic, and operative characteristics as well as outcomes were assessed using standard univariate statistical methods. Multivariate logistic regression models were fit to assess for independent contributions to the primary and secondary outcomes., Results: Following exclusions, 78 patients were available for analysis. Of these patients, 38 (48.7%) had HBH reversal and 40 (51.3%) had persistent HBH on postnatal MRI. Baseline demographic and preoperative ultrasound characteristics were similar between groups. The primary outcome of CSF diversion within the 1st year of life was similar between the two groups (42.1% vs 57.5%, p = 0.17). All secondary outcomes were also similar between groups. Patients who had occurrence of the primary outcome had greater presurgical lateral ventricle width than those who did not (16.1 vs 12.1 mm, p = 0.02) when HBH was reversed, but not when HBH was persistent (12.5 vs 10.7 mm, p = 0.49). In multivariate analysis, presurgical lateral ventricle width was associated with increased rates of CSF diversion before 12 months of life (adjusted OR 1.18, 95% CI 1.03-1.35) and CSF diversion prior to NICU discharge (adjusted OR 1.18, 95% CI 1.02-1.37)., Conclusions: HBH reversal was not associated with decreased rates of CSF diversion in this cohort. Predictive accuracy of the anticipated benefits of prenatal NTD repair may not be augmented by the observation of HBH reversal on MRI.

The basic pattern of arterial vascularization is highly conserved across vertebrates and develops under neuromeric rules. The hindbrain has an angioarchitecture that is homologous to that of the spinal cord, and the hindbrain vascular system can be analyzed at the longitudinal and axial structures. During development, there are two main longitudinal arteries: the longitudinal neural artery and primitive lateral basilovertebral anastomosis. This review discusses the basic pattern of the blood supply of the hindbrain, the development of vascularization, and the anatomical variations, with a special reference to the embryological point of view of two main longitudinal anastomoses (longitudinal neural artery and primitive lateral basilovertebral anastomosis). The formation of commonly observed variations, such as fenestration and duplication of the vertebrobasilar artery, or primitive trigeminal artery variant, can be explained by the partial persistence of the primitive lateral basilovertebral anastomosis. Understanding the pattern and the development of the blood supply of the hindbrain provides useful information of the various anomalies of the vertebrobasilar junction and cerebellar arteries.

Chiari malformation is characterised by the herniation of the cerebellar tonsils through the foramen magnum. However, tonsillar herniation and other 2D morphometric measurements of the posterior cranial fossa (PCF) have a weak association with patients' symptoms and clinical outcomes. This study aimed to contrast current 2D metrics with a novel 3D shape analysis of the PCF and the hindbrain, to determine if 3D measurements provides further insight into the pathophysiology of Chiari. The cranium of 12 controls and 21 Chiari malformation patients with (N = 9) and without (N = 12) a syrinx were scanned. The morphology of the PCF was quantified with typical 2D measurements. Additionally, a correspondence-based shape model that normalised the PCF volume, was used to find 3D differences in the shape of the PCF, and the distance of the hindbrain from the inner surfaces of the PCF. Shape analysis showed that, compared to controls, the caudal (p = 0.007; 2.3 mm, IQR: 1.6-3.3 mm) and anterior (p = 0.027; 1.3 mm,IQR: 1.1-1.6 mm) surfaces of the hindbrain were closer to the PCF in patients with and without a syrinx, respectively. However, there were negligible differences in the shape of the PCF between patient groups (p > 0.39). Current morphometric measures should be normalised for variation in PCF volume, so that shape measures are not biased. The reduced CSF space between the hindbrain and PCF will alter CSF dynamics, which may compress cerebellar vasculature and contribute to patient symptomatology., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: To provide a detailed description of the sonographic appearance and development of various fetal structures of the midbrain and hindbrain (MBHB) during the early second trimester, and to evaluate the impact of the frequency of the transvaginal sonography (TVS) transducer on the early recognition of these structures., Methods: This was a retrospective analysis of three-dimensional volumetric datasets of the MBHB from apparently normal fetuses at 14-19 gestational weeks, acquired by TVS in the midsagittal view through the posterior fontanelle. Using a multiplanar approach, we measured the tectal thickness and length, aqueductal thickness, tegmental thickness and width and height of the Blake's pouch (BP) neck. In addition, we assessed the existence of early vermian fissures, the linear shape of the brainstem and the components of the fastigium. The correlation between gestational age according to last menstrual period and sonographic measurements of MBHB structures was evaluated using Pearson's correlation (r). A subanalysis was performed to assess the performance of a 5-9-MHz vs a 6-12-MHz TVS transducer in visualizing the MBHB structures in the early second trimester., Results: Sixty brain volumes were included in the study, obtained at a mean gestational age of 16.2 weeks (range, 14.1-19.0 weeks), with a transverse cerebellar diameter range of 13.0-19.8 mm. We found a strong correlation between gestational age and all MBHB measurements, with the exception of the tectal, tegmental and aqueductal thicknesses, for which the correlation was moderate. There was good-to-excellent intraobserver and moderate-to-good interobserver correlation for most MBHB measurements. We observed that the BP neck was patent in all fetuses between 14 and 18 weeks with decreasing diameter, and that the aqueductal thickness was significantly smaller at ≥ 18 weeks compared with at < 16 weeks. The early vermian fissures and the linear shape of the brainstem were present in all fetuses from 14 weeks. We found that, in the early second trimester, the horizontal arm of the presumed 'fastigium' evolves from the fourth ventricular choroid plexus and not the posterior vermis, indicating that this is not the fastigium. Standard- and high-resolution TVS transducers performed similarly in the assessment of MBHB anatomy., Conclusion: Detailed early second-trimester assessment of the MBHB is feasible by transvaginal neurosonography and provides reference data which may help in the early detection of brain pathology involving the MBHB. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: To describe the prenatal neuroimaging spectrum of rhombencephalosynapsis (RES) and criteria for its classification according to the severity of vermian anomaly., Methods: In this multicenter retrospective study of fetuses with RES between 2002 and 2020, the medical records and brain ultrasound and magnetic resonance images were evaluated comprehensively to determine the severity of the vermian anomaly and the presence of associated brain findings. RES was classified, according to the pattern of vermian agenesis and the extent of the fusion of the hemispheres, as complete RES (complete absence of the vermis) or partial RES (further classified according to the part of the vermis that was missing and, consequently, the region of hemispheric fusion, as anterior, posterior, severe or mixed RES). Findings were compared between cases with complete and those with partial RES., Results: Included in the study were 62 fetuses with a gestational age ranging between 12 and 37 weeks. Most had complete absence of the vermis (complete RES, 77.4% of cases), a 'round-shaped' cerebellum on axial views (72.6%) and a transverse cerebellar diameter (TCD) < 3 rd centile (87.1%). Among the 22.6% of cases with partial RES, 6.5% were classified as severe partial, 6.5% as partial anterior, 8.1% as partial mixed and 1.6% as partial posterior. Half of these cases presented with normal or nearly normal cerebellar morphology and 28.5% had a TCD within the normal limits. Infratentorially, the fourth ventricle was abnormal in 88.7% of cases overall, and anomalies of the midbrain and pons were frequent (93.5% and 77.4%, respectively). Ventriculomegaly was observed in 80.6% of all cases, being more severe in cases with complete RES than in those with partial RES, with high rates of parenchymal and septal disruption., Conclusions: This study provides prenatal neuroimaging criteria for the diagnosis and classification of RES, and identification of related features, using ultrasound and magnetic resonance imaging. According to our findings, a diagnosis of RES should be considered in fetuses with a small TCD (severe cerebellar hypoplasia) and/or a round-shaped cerebellum on axial views, during the second or third trimester, especially when associated with ventriculomegaly. Partial RES is more common than previously thought, but presents an extreme diagnostic challenge, especially in cases with normal or nearly-normal cerebellar morphobiometric features. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

Purpose:  The aim was to describe the sonographic follow-up of hindbrain herniation (HH), the banana and lemon sign after fetal myelomeningocele (fMMC) repair, and the time of disappearance of these signs after the intervention, and to investigate any predictive value for the necessity of shunting during the infant's first year of life. Additionally, the sonographic evolution of the transcerebellar diameter (TCD) before and after fetal intervention was assessed., Patients and Methods:  The first 50 patients that underwent fMMC repair at Zurich Center for Fetal Diagnosis and Therapy (www.swissfetus.ch) were included in this study. Sonographic scans performed weekly after fMMC repair focusing on HH and banana and lemon signs were analyzed and compared between the shunted and the non-shunted group. ROC curves were generated for the time intervals of resolution of the signs in order to show their predictive accuracy for the need for shunting until 1 year of age., Results:  HH resolved in 48 fetuses (96 %) before delivery. The sonographic disappearance of HH within the first two weeks after fMMC repair was associated with a significantly lower incidence of shunt placement (OR 0.19; 95 % CI 0.4-0.9) during the first year of life (p = 0.03). All fetuses with persistent HH before delivery received a shunt. TCD growth was observed in all fetuses., Conclusion:  The reversibility of HH within two weeks after fMMC repair is associated with an 80 % lower incidence of shunt placement during the infant's first year of life. Moreover, it allows the cerebellum to grow and to normalize its configuration., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

A wide number of neurological manifestations have been described in association with coronavirus disease 19 (COVID-19). We describe an unusual case of a young man who developed severe rhombencephalitis after COVID-19. He demonstrated clinical and radiological improvement with high dose corticosteroids, plasma exchange and intravenous immune globulin. Our findings, along with previously reported cases that we review here, support an autoimmune para- or post-infectious mechanism and highlight a possible role for immunotherapy in patients with rhombencephalitis after COVID-19., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Listeria monocytogenes is a Gram-positive facultative intracellular bacterium that causes central nervous system infection. We report a case of rhombencephalitis caused by L. monocytogenes infection, which mimicked Bickerstaff's brainstem encephalitis, and GQ1b antibody positivity and multiple intracranial foci were observed. A 68-year-old male patient presented with a nonspecific prodrome of faintness, forehead tightness, and walking instability. This was followed by progressive cranial nerve palsies, limb weakness, cerebellar signs, hyperpyrexia, and impaired consciousness. Brain imaging showed multiple abnormal brainstem and cerebellar signals that were accompanied by blood infiltration without any lesion enhancement. Serum GQ1b antibody positivity led to an initial diagnosis of Bickerstaff's brainstem encephalitis, which was treated with immunosuppressive therapy with limited efficacy. A pathogen examination helped confirm L. monocytogenes infection. A combination of meropenem and trimethoprim-sulfamethoxazole therapy was applied and the patient recovered without sequelae. The symptoms and imaging of Listeria rhombencephalitis are nonspecific. Accurate diagnosis and prompt treatment of this condition are essential. Whether Listeria infection triggers an autoimmune response remains unclear.

We aim to characterize patients with Gomez-López-Hernández syndrome (GLHS) clinically and to investigate them molecularly. A clinical protocol, including a morphological and neuropsychological assessment, was applied to 13 patients with GLHS. Single-nucleotide polymorphism (SNP) array and whole-exome sequencing were undertaken; magnetic resonance imaging was performed in 12 patients, including high-resolution, heavily T2-weighted sequences (HRT2) in 6 patients to analyze the trigeminal nerves. All patients presented alopecia; two did not present rhombencephalosynapsis (RES); trigeminal anesthesia was present in 5 of the 11 patients (45.4%); brachycephaly/brachyturricephaly and mid-face retrusion were found in 84.6 and 92.3% of the patients, respectively. One patient had intellectual disability. HRT2 sequences showed trigeminal nerve hypoplasia in four of the six patients; all four had clinical signs of trigeminal anesthesia. No common candidate gene was found to explain GLHS phenotype. RES does not seem to be an obligatory finding in respect of GLHS diagnosis. We propose that a diagnosis of GLHS should be considered in patients with at least two of the following criteria: focal non-scarring alopecia, rhombencephalosynapsis, craniofacial anomalies (brachyturrycephaly, brachycephaly or mid-face retrusion), trigeminal anesthesia or anatomic abnormalities of the trigeminal nerve. Studies focusing on germline whole genome sequencing or DNA and/or RNA sequencing of the alopecia tissue may be the next step for the better understanding of GLHS etiology., (© 2020 Wiley Periodicals LLC.)

Listeria rhombencephalitis (L. rhombencephalitis) is an uncommon form of central nervous system infection caused by Listeria monocytogenes (LM). It often occurs to immunocompetent individuals. Here, we described the case of a 45-year-old female patient without medical histories, who presented for high-grade fever, headache, and focal neurological manifestations. She was initially empirically diagnosed with acute disseminated encephalomyelitis (ADEM) because of clinical symptoms, acute clinical course, and neuroimaging. However, the biochemical analysis of cerebral spinal fluid (CSF) questioned the diagnosis of ADEM. The final diagnosis of L. rhombencephalitis was based on CSF culture for LM. Thus, L. rhombencephalitis should be preferentially and empirically considered for a patient with significantly elevated lactic acid and moderately increased red cells in CSF at early time, accompanied with rapidly progressive neurological dysfunctions involved in the brain stem.

Background and Purpose: Fetal imaging is crucial in the evaluation of open neural tube defects. The identification of intraventricular hemorrhage prenatally has unclear clinical implications. We aimed to explore fetal imaging findings in open neural tube defects and evaluate associations between intraventricular hemorrhage with prenatal and postnatal hindbrain herniation, postnatal intraventricular hemorrhage, and ventricular shunt placement., Materials and Methods: After institutional review board approval, open neural tube defect cases evaluated by prenatal sonography between January 1, 2013 and April 24, 2018 were enrolled ( n = 504). The presence of intraventricular hemorrhage and gray matter heterotopia by both prenatal sonography and MR imaging studies was used for classification. Cases of intraventricular hemorrhage had intraventricular hemorrhage without gray matter heterotopia ( n = 33) and controls had neither intraventricular hemorrhage nor gray matter heterotopia ( n = 229). A total of 135 subjects with findings of gray matter heterotopia were excluded. Outcomes were compared with regression analyses., Results: Prenatal and postnatal hindbrain herniation and postnatal intraventricular hemorrhage were more frequent in cases of prenatal intraventricular hemorrhage compared with controls (97% versus 79%, 50% versus 25%, and 63% versus 12%, respectively). Increased third ventricular diameter, specifically >1 mm, predicted hindbrain herniation (OR = 3.7 [95% CI, 1.5-11]) independent of lateral ventricular size and prenatal intraventricular hemorrhage. Fetal closure ( n = 86) was independently protective against postnatal hindbrain herniation (OR = 0.04 [95% CI, 0.01-0.15]) and postnatal intraventricular hemorrhage (OR = 0.2 [95% CI, 0.02-0.98]). Prenatal intraventricular hemorrhage was not associated with ventricular shunt placement., Conclusions: Intraventricular hemorrhage is relatively common in the prenatal evaluation of open neural tube defects. Hindbrain herniation is more common in cases of intraventricular hemorrhage, but in association with increased third ventricular size. Fetal closure reverses hindbrain herniation and decreases the rate of intraventricular hemorrhage postnatally, regardless of the presence of prenatal intraventricular hemorrhage., (© 2020 by American Journal of Neuroradiology.)

Hunger and thirst have distinct goals but control similar ingestive behaviors, and little is known about neural processes that are shared between these behavioral states. We identify glutamatergic neurons in the peri-locus coeruleus (periLC VGLUT2 neurons) as a polysynaptic convergence node from separate energy-sensitive and hydration-sensitive cell populations. We develop methods for stable hindbrain calcium imaging in free-moving mice, which show that periLC VGLUT2 neurons are tuned to ingestive behaviors and respond similarly to food or water consumption. PeriLC VGLUT2 neurons are scalably inhibited by palatability and homeostatic need during consumption. Inhibition of periLC VGLUT2 neurons is rewarding and increases consumption by enhancing palatability and prolonging ingestion duration. These properties comprise a double-negative feedback relationship that sustains food or water consumption without affecting food- or water-seeking. PeriLC VGLUT2 neurons are a hub between hunger and thirst that specifically controls motivation for food and water ingestion, which is a factor that contributes to hedonic overeating and obesity., Competing Interests: Declaration of Interests S.M.S. has served on the Scientific Advisory Board of Inscopix, Inc. and owns stock in the company., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In children with rhombencephalitis, neuroimaging abnormalities have been infrequently correlated with clinical outcome. We investigated whether magnetic resonance (MR) neuroimaging studies could predict clinical outcomes and disturbance of consciousness in patients with rhombencephalitis. We retrospectively analyzed the MR studies of 19 pediatric patients with rhombencephalitis (median age: 4.2 years, range 0.5-17; sex: 32% male). Fluid-attenuated inversion recovery imaging and diffusion-weighted imaging findings were graded to create imaging scores according to the extent of imaging abnormality. Clinical outcomes in the first week and 12th month were graded by using Glasgow Outcome Scale scores (1-5) and dichotomized to unfavorable or favorable outcome. Correlations of the imaging scores with the clinical outcomes and with disturbance of consciousness were assessed by using multivariate logistic regression analysis. No significant correlation was found between fluid-attenuated inversion recovery score or diffusion-weighted imaging score ( P = .608, P = .132, respectively) and disturbance of consciousness. In the first week, the unfavorable outcome group (n = 11) had significantly higher diffusion-weighted imaging score than did the favorable outcome group (n = 8) (Mann-Whitney U test, P = .005). Multivariate logistic regression analysis showed that the diffusion-weighted imaging score (odds ratio, 18.182; 95% confidence interval: 1.36, 243.01; P = .028) was significantly associated with unfavorable outcome. In the 12th month, the fluid-attenuated inversion recovery score or diffusion-weighted imaging score ( P = .994, P = .997, respectively) were not significantly associated with unfavorable outcome. Patients with rhombencephalitis who have a higher diffusion-weighted imaging score are more likely to have an unfavorable 1-week clinical outcome.

Competing Interests: Competing interests: None declared.

Purpose: Chiari malformations (CM) have been traditionally classified into four categories: I, II, III, and IV. In light of more recent understandings, variations of the CM have required a modification of this classification., Methods: This article discusses the presentation, diagnostics, and treatment of the newer forms of hindbrain herniation associated with the CM type I., Results: The CM 1 is a spectrum that includes some patients who do not fall into the exact category of this entity., Conclusions: While CM have been categorically recognized as discrete and individual conditions, newer classifications such as CM 0 and CM 1.5 exhibit some degree of continuity with CM 1; however, they require distinct and separate classification as symptoms and treatments can vary among these clinical subtypes.

Background: Chiari II malformation includes concomitant cerebellar tonsillar herniation, hydrocephalus, and myelomeningocele. Rarely, pediatric patients with persistent hindbrain herniation develop a new enhancing nodule at the cervicomedullary junction as adults. These new lesions may be suspicious for neoplastic growth, but it remains unclear if neurosurgical intervention is necessary., Case Report: A 27-year-old female patient with history of Chiari II malformation and persistent hindbrain herniation presented with a 3-month history of headache and upper extremity weakness and numbness. Neuroimaging revealed a new enhancing nodule near the cervicomedullary junction suspicious for neoplasm. Following posterior fossa decompression and excision of the enhancing lesion, pathological analysis demonstrated only benign glioneural heterotopia., Results: New enhancing nodules at the cervicomedullary junction in Chiari II malformation are exceedingly rare and are likely benign, reactive changes rather than a neoplastic process. Biopsy or surgical excision of these lesions is likely unnecessary for asymptomatic patients.

Objective: Prenatal diagnosis of midbrain-hindbrain (MB-HB) malformations relies primarily on abnormal size and shape of the cerebellum and retrocerebellar space, particularly 'open fourth ventricle' (4V), the most common indicator of MB-HB malformations. The aim of this study was to present the fourth ventricle index (4VI), and to evaluate its role as a marker for severe vermian dysgenesis/agenesis in cases without open 4V., Methods: This was a prospective cross-sectional study of patients with singleton low-risk pregnancy at 14 + 1 to 36 + 6 gestational weeks presenting between May 2016 and November 2017 for routine ultrasound examination. Axial images of the fetal 4V were obtained and the 4VI was calculated as the ratio between the laterolateral and the anteroposterior diameters. Reference ranges were constructed and retrospectively collected values from 44 fetuses with confirmed anomalies involving severe vermian dysgenesis/agenesis (Joubert syndrome and related disorders, rhombencephalosynapsis, cobblestone malformations and cerebellar hypoplasia) but without open 4V were compared with the normal values., Results: In total, 384 healthy fetuses were enrolled into the study, from which reference ranges were produced, and 44 cases were collected retrospectively. The 4VI in the normal fetuses was always > 1. In affected fetuses, it was always below mean -2 SD and < 1., Conclusions: The 4VI is a sonographic marker for severe fetal vermian dysgenesis/agenesis in the absence of an open 4V. It may be incorporated easily into the routine brain scan; 4VI < 1 indicates a need for dedicated fetal neuroimaging for diagnosis and prenatal counseling. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.)

The hypothalamic-pituitary-adrenal (HPA) axis regulates responses to internal and external stressors. Many patients diagnosed with conditions such as depression or anxiety also have hyperactivity of the HPA axis. Hyper-stimulation of the HPA axis results in sustained elevated levels of glucocorticoids which impair neuronal function and can ultimately result in a psychiatric disorder. Studies investigating Glucocorticoid Receptor (GR/NR3C1) in the brain have primarily focused on the forebrain, however in recent years, the hindbrain has become a region of interest for research into the development of anxiety and depression, though the role of GR signalling in the hindbrain remains poorly characterised. To determine the role of glucocorticoid signalling in the hindbrain we have developed a novel mouse model that specifically ablates hindbrain GR to ascertain its role in behaviour, HPA-axis regulation and adrenal structure. Our study highlights that ablation of GR in the hindbrain results in excessive barbering, obsessive compulsive digging and lack of cage exploration. These mice also develop kyphosis, elevated circulating corticosterone and severe adrenal cortex disruption. Together, this data demonstrates a role for hindbrain GR signalling in regulating stress-related behaviour and identifies a novel mouse model to allow further investigation into the pathways impacting stress and anxiety.

A 46-year-old previously healthy man presented with 1 week of headache, nausea, vomiting and dizziness. He was found to have cranial nerve deficits, his cerebrospinal fluid (CSF) demonstrated a lymphocytic pleocytosis and brain MRI suggested rhombencephalitis. Although Gram stains and cultures of his CSF did not identify a pathogen, Listeria monocytogenes DNA was detected by the FilmArray Meningitis/Encephalitis panel within 2 hours of performing a lumbar puncture. He was treated with ampicillin and gentamicin and had a near-complete recovery. This case highlights the importance of recognising L. monocytogenes infection as a cause of acute cranial nerve impairment with MRI findings suggestive of brainstem encephalitis. It also highlights the frequently atypical CSF profile and low yield of culture in L. monocytogenes rhombencephalitis and the value of multiplex PCR testing of CSF to rapidly identify this pathogen and permit targeted therapy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Extreme microcephaly and rhombencephalosynapsis represent unusual pathological conditions, each of which occurs in isolation or in association with various other cerebral and or extracerebral anomalies. Unlike microcephaly for which several disease-causing genes have been identified with different modes of inheritance, the molecular bases of rhombencephalosynapsis remain unknown and rhombencephalosynapsis presents mainly as a sporadic condition consistent with de novo dominant variations. We report for the first time the association of extreme microcephaly with almost no sulcation and rhombencephalosynapsis in a fœtus for which comparative patient-parent exome sequencing strategy revealed a heterozygous de novo missense variant in the ADGRL2 gene. ADGRL2 encodes latrophilin 2, an adhesion G-protein-coupled receptor whose exogenous ligand is α-latrotoxin. Adgrl2 immunohistochemistry and in situ hybridization revealed expression in the telencephalon, mesencephalon and rhombencephalon of mouse and chicken embryos. In human brain embryos and fœtuses, Adgrl2 immunoreactivity was observed in the hemispheric and cerebellar germinal zones, the cortical plate, basal ganglia, pons and cerebellar cortex. Microfluorimetry experiments evaluating intracellular calcium release in response to α-latrotoxin binding showed significantly reduced cytosolic calcium release in the fœtus amniocytes vs amniocytes from age-matched control fœtuses and in HeLa cells transfected with mutant ADGRL2 cDNA vs wild-type construct. Embryonic lethality was also observed in constitutive Adgrl2 -/- mice. In Adgrl2 +/- mice, MRI studies revealed microcephaly and vermis hypoplasia. Cell adhesion and wound healing assays demonstrated that the variation increased cell adhesion properties and reduced cell motility. Furthermore, HeLa cells overexpressing mutant ADGRL2 displayed a highly developed cytoplasmic F-actin network related to cytoskeletal dynamic modulation. ADGRL2 is the first gene identified as being responsible for extreme microcephaly with rhombencephalosynapsis. Increased cell adhesion, reduced cell motility and cytoskeletal dynamic alterations induced by the variant therefore represent a new mechanism responsible for microcephaly.

Thermosensation provides crucial information, but how temperature representation is transformed from sensation to behavior is poorly understood. Here, we report a preparation that allows control of heat delivery to zebrafish larvae while monitoring motor output and imaging whole-brain calcium signals, thereby uncovering algorithmic and computational rules that couple dynamics of heat modulation, neural activity and swimming behavior. This approach identifies a critical step in the transformation of temperature representation between the sensory trigeminal ganglia and the hindbrain: A simple sustained trigeminal stimulus representation is transformed into a representation of absolute temperature as well as temperature changes in the hindbrain that explains the observed motor output. An activity constrained dynamic circuit model captures the most prominent aspects of these sensori-motor transformations and predicts both behavior and neural activity in response to novel heat stimuli. These findings provide the first algorithmic description of heat processing from sensory input to behavioral output., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) associated disorders present with a spectrum of clinical pictures including brainstem involvement., Case Report: A patient with the sudden onset of a post-partum severe rhombencephalitis causing respiratory failure (12 years after a mild transverse myelitis). Despite the aggressive clinical course, she had an impressive recovery after plasmapheresis, and no further relapses on immunosuppression., Conclusion: MOG-IgG disorders could relapse several years after onset and involve brainstem. Good prognosis is possible after treatment., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: Type I Chiari malformation (CMI) is a radiologically-defined structural dysmorphism of the hindbrain and posterior cranial fossa (PCF). Traditional radiographic identification of CMI relies on the measurement of the cerebellar tonsils in relation to the foramen magnum with or without associated abnormalities of the neuraxis. The primary goal of this retrospective study was to comprehensively assess morphometric parameters above the McRea line in a group of female CMI patients and normal controls., Material and Methods: Twenty-nine morphological measurements were taken on 302 mid-sagittal MR images of adult female CMI patients (n=162) and healthy controls (n=140). All MR images were voluntarily provided by CMI subjects through an online database and control participant images were obtained through the Human Connectome Project and a local hospital system., Results: Analyses were performed on the full dataset of adult female MR images and a restricted dataset of 229 participants that were equated for age, race, and body mass index. Eighteen group differences were identified in the PCF area that we grouped into three clusters; PCF structures heights, clivus angulation, and odontoid process irregularity. Fourteen group differences persisted after equating our CMI and control groups on demographic characteristics., Conclusion: PCF structures reliably differ in adult female CMI patients relative to healthy controls. These differences reflect structural abnormalities in the osseous and soft tissue structures of the clivus, odontoid process, and cerebellum. Clinical and pathophysiological implications are discussed., (Copyright © 2017. Published by Elsevier Masson SAS.)

Neurovascular conflict (NVC) has been postulated to be the underlying cause of trigeminal neuralgia (TN). Does the posterior fossa crowdedness increase the chance of NVC? The aim of this study was to quantitatively measure the posterior fossa crowdedness in patients with TN and to perform a comparison with healthy controls. We conducted a prospective case-control study of 46 patients diagnosed with primary TN and 46 sex- and age-matched healthy controls. All subjects underwent high-resolution three-dimensional MRI, and the 3D Slicer software was used to measure the posterior fossa volume (PFV) and hindbrain volume (HBV). The posterior fossa crowdedness index (PFCI) was calculated as HBV/PFV × 100%. The results showed that patients with TN had a larger HBV (155.4 ± 23.2 cm 3 versus 152.9 ± 13.5 cm 3 , P = .16) and a smaller PFV (182.7 ± 18.3 cm 3 versus 186.1 ± 11.7 cm 3 , P = .42) as compared to control subjects, but these values were not significantly different. The mean PFCI was significantly higher in patients with TN than in controls (85.1% ± 3.4% versus 82.2% ± 5.3%; P = .03). Women had a more crowded posterior fossa than men (85.8% ± 2.1% versus 84.1% ± 2.6%; P = .023) in patients with TN. The correlation analysis showed that a higher PFCI was associated with younger age (P = .02), woman (P = .014), and TN disease (P = .001). From this study, we conclude that patients with TN have a more crowded posterior fossa than healthy subjects. Women, younger age and TN disease are associated with a higher PFCI. The posterior fossa crowdedness may be a risk factor of NVC, and thus more likely to result in the genesis of TN., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Listeria monocytogenes is associated with rhombencephalitis. However, the exact mechanisms of brainstem invasion remains poorly understood. Here, we demonstrate clinical and radiological data suggesting that Listeria may invade the brainstem via the trigeminal nerve. Three females (41, 64 and 70 years) with culture proven L. monocytogenes bacteremia and rhombencephalitis were investigated in the period of 2014-16. T2-weighted and contrast-enhanced T1-weighted MRI revealed a cerebellopontine abscess in all three patients, including the involvement of the trigeminal nerve root. In two patients, MRI also revealed selective contrast enhancement of the sensory trigeminal tract in the pons and medulla oblongata. Prior to any other neurological symptoms, two patients complained of hypoesthesia and a tingling sensation in the ipsilateral half of the face, consistent with sensory trigeminal nerve dysfunction on that side. In addition, we identified another 120 cases of Listeria rhombencephalitis following a systematic review. Cranial nerves VII, V, IX, and X, respectively, medulla oblongata, cerebellum and pons, were the most frequently involved brain structures. The present clinical and radiological findings corroborate earlier data from animal experiments, indicating that L. monocytogenes may be capable of retrograde intra-axonal migration along the cranial nerves. We suggest that in a subset of patients with rhombencephalitis L. monocytogenes enters the cerebellopontine angle through the trigeminal nerve, invading the brainstem via the sensory trigeminal nuclei.

Background and Purpose: As the practice of in utero repair of myelomeningoceles becomes more prevalent, knowledge of the expected MR imaging findings has become increasingly important. Our aim was to examine neuroimaging findings with a focus on hindbrain herniation and ventricular size in fetuses with open spinal dysraphism and to compare them with postnatal imaging features in groups undergoing prenatal-versus-postnatal repair., Materials and Methods: Single-center retrospective analysis was performed on MRIs of fetuses with open spinal dysraphism from January 2004 through July 2015 with available postnatal imaging. One hundred two fetuses were included. Reports from available fetal ultrasound were also examined. Images were reviewed by 2 board-certified fellowship-trained pediatric neuroradiologists. Descriptive analyses were performed to demonstrate the distribution of the imaging findings., Results: Thirty-two of 102 (31.3%) fetuses underwent in utero repair of open spinal dysraphism; 68.6% (70/102) underwent postnatal repair. Ninety-four of 102 (92.2%) fetuses had cerebellar ectopia. Of those who underwent prenatal repair (26 grade 3, 6 grade 2), 81.3% (26/32) had resolved cerebellar ectopia postnatally. Of those who had severe cerebellar ectopia (grade 3) that underwent postnatal repair, 65.5% (36/55) remained grade 3, while the remaining 34.5% (19/55) improved to grade 2. The degree of postnatal lateral ventriculomegaly in those that underwent prenatal repair (20.3 ± 5.6 mm) was not significantly different from that in those that underwent postnatal repair (21.5 ± 10.2 mm, P = .53). Increased Chiari grade was significantly correlated with decreased head size for gestational age on fetal sonography ( P = .0054)., Conclusions: In fetuses with open spinal dysraphism and severe Chiari II malformation that do not undergo prenatal repair, most have no change in the severity of cerebellar ectopia/Chiari grade. However, in fetuses that undergo in utero repair, most have resolved cerebellar ectopia postnatally., (© 2017 by American Journal of Neuroradiology.)

Mid-hindbrain malformations can occur during embryogenesis through a disturbance of transient and localized gene expression patterns within these distinct brain structures. Rho guanine nucleotide exchange factor (ARHGEF) family members are key for controlling the spatiotemporal activation of Rho GTPase, to modulate cytoskeleton dynamics, cell division, and cell migration. We identified, by means of whole exome sequencing, a homozygous frameshift mutation in the ARHGEF2 as a cause of intellectual disability, a midbrain-hindbrain malformation, and mild microcephaly in a consanguineous pedigree of Kurdish-Turkish descent. We show that loss of ARHGEF2 perturbs progenitor cell differentiation and that this is associated with a shift of mitotic spindle plane orientation, putatively favoring more symmetric divisions. The ARHGEF2 mutation leads to reduction in the activation of the RhoA/ROCK/MLC pathway crucial for cell migration. We demonstrate that the human brain malformation is recapitulated in Arhgef2 mutant mice and identify an aberrant migration of distinct components of the precerebellar system as a pathomechanism underlying the midbrain-hindbrain phenotype. Our results highlight the crucial function of ARHGEF2 in human brain development and identify a mutation in ARHGEF2 as novel cause of a neurodevelopmental disorder.

Ocular flutter is a dramatic clinical sign that poses multiple diagnostic considerations. The case description outlines a well young male that presented with ocular flutter and truncal ataxia. The clinical syndrome was subsequently attributed to enteroviral rhombencephalitis. The mechanism and neuroanatomical correlates are discussed, and potential treatments considered., (Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.)

Objectives: To characterise the symptomatic phenotype of Chiari-like malformation (CM), secondary syringomyelia (SM) and brachycephaly in the Cavalier King Charles Spaniel using morphometric measurements on mid-sagittal Magnetic Resonance images (MRI) of the brain and craniocervical junction., Methods: This retrospective study, based on a previous quantitative analysis in the Griffon Bruxellois (GB), used 24 measurements taken on 130 T1-weighted MRI of hindbrain and cervical region. Associated brachycephaly was estimated using 26 measurements, including rostral forebrain flattening and olfactory lobe rotation, on 72 T2-weighted MRI of the whole brain. Both study cohorts were divided into three groups; Control, CM pain and SM and their morphometries compared with each other., Results: Fourteen significant traits were identified in the hindbrain study and nine traits in the whole brain study, six of which were similar to the GB and suggest a common aetiology. The Control cohort had the most elliptical brain (p = 0.010), least olfactory bulb rotation (p = 0.003) and a protective angle (p = 0.004) compared to the other groups. The CM pain cohort had the greatest rostral forebrain flattening (p = 0.007), shortest basioccipital (p = 0.019), but a greater distance between the atlas and basioccipital (p = 0.002) which was protective for SM. The SM cohort had two conformation anomalies depending on the severity of craniocervical junction incongruities; i) the proximity of the dens (p <0.001) ii) increased airorhynchy with a smaller, more ventrally rotated olfactory bulb (p <0.001). Both generated 'concertina' flexures of the brain and craniocervical junction., Conclusion: Morphometric mapping provides a diagnostic tool for quantifying symptomatic CM, secondary SM and their relationship with brachycephaly. It is hypothesized that CM pain is associated with increased brachycephaly and SM can result from different combinations of abnormalities of the forebrain, caudal fossa and craniocervical junction which compromise the neural parenchyma and impede cerebrospinal fluid flow., Competing Interests: SPK is a post-graduate research student and CC an undergraduate at the University of Surrey where CR and RMLR are employed. ZK is employed by Montreal University. JJ, CD, AT and CR are employed by Fitzpatrick Referrals Ltd, Surrey, GU7 Q22. SG is employed by the Goddard Veterinary Group, Stone Lion Veterinary Hospital, SW19 5AU. AKM is an independent statistical consultant operating professionally as a sole trader under the company name of akm-stats and did not receive any salary or other remittance for his contribution in this investigation. The University of Surrey, Montreal University, Fitzpatrick Referrals Ltd, Goddard Veterinary Group did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials. None of the authors have personal or financial relationships with other people or organizations that might inappropriately influence or bias the content of the paper. There are no patents, products in development, or marketed products to declare. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Objectives: To characterize and compare the phenotypic variables of the hindbrain and craniocervical junction associated with syringomyelia (SM) in the Chihuahua, Affenpinscher and Cavalier King Charles Spaniel (CKCS)., Method: Analysis of 273 T1-weighted mid-sagittal DICOM sequences of the hindbrain and craniocervical junction from 99 Chihuahuas, 42 Affenpinschers and 132 CKCSs. The study compared 22 morphometric features (11 lines, eight angles and three ratios) of dogs with and without SM using refined techniques based on previous studies of the Griffon Bruxellois (GB) using Discriminant Function Analysis and ANOVA with post-hoc corrections., Results: The analysis identified 14/22 significant traits for SM in the three dog breeds, five of which were identical to those reported for the GB and suggest inclusion of a common aetiology. One ratio, caudal fossa height to the length of the skull base extended to an imaginary point of alignment between the atlas and supraoccipital bones, was common to all three breeds (p values 0.029 to <0.001). Associated with SM were a reduced occipital crest and two acute changes in angulation i) 'sphenoid flexure' at the spheno-occipital synchondrosis ii) 'cervical flexure' at the foramen magnum allied with medulla oblongata elevation. Comparing dogs with and without SM, each breed had a unique trait: Chihuahua had a smaller angle between the dens, atlas and basioccipital bone (p value < 0.001); Affenpinschers had a smaller distance from atlas to dens (p value 0.009); CKCS had a shorter distance between the spheno-occipital synchondrosis and atlas (p value 0.007)., Conclusion: The selected morphometries successfully characterised conformational changes in the brain and craniocervical junction that might form the basis of a diagnostic tool for all breeds. The severity of SM involved a spectrum of abnormalities, incurred by changes in both angulation and size that could alter neural parenchyma compliance and/or impede cerebrospinal fluid channels., Competing Interests: SPK is a post graduate research student at the University of Surrey where CR and RMLaR are employed. CR is also are employed by Fitzpatrick Referrals Ltd, Surrey. A-MK and TJ are employed by the University of Helsinki. AKM is an independent statistical consultant operating professionally as a sole trader under the company name of akmstats and did not receive any salary or other remittance for his contribution in this investigation. Fitzpatrick Referrals Ltd and the Universites of Surrey and Finland did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials. None of the authors have personal or financial relationships with other people or organizations that might inappropriately influence or bias the content of the paper. There are no patents, products in development, or marketed products to declare. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Background: Positional plagiocephaly is the most common cause of cranial asymmetry. The underlying cause of Chiari-1 malformation has many possible theories, and anecdotally some pediatric neurosurgeons have had experience of severe cases of positional brachycephaly with Chiari-1. However, to date, there have been no published cases linking nonsynostotic plagiocephaly with Chiari-1 malformation., Case Description: An 18-month-old boy presented with a head injury. On examination he had a Glasgow Coma Score of 15 with no focal neurologic deficits, but he was noted to have marked posterior brachycephaly. A computed tomography scan showed a slim left-sided hemispheric acute subdural hematoma with no mass effect, which was treated conservatively. Of note, all of his cranial vault sutures were open, and a diagnosis of incidental positional plagiocephaly was made. Subsequent magnetic resonance imaging as part of a work-up to exclude nonaccidental injury showed a small posterior fossa with a steep tentorium and herniation of the cerebellar tonsils to the level of the body of the second cervical vertebra., Conclusions: Chronic hindbrain herniation is well reported in cases of craniosynostosis, but to our knowledge this is the first published case associated with nonsynostotic deformational plagiocephaly. We hypothesize that severe posterior plagiocephaly can cause disproportion of the posterior fossa: hindbrain volume ratio and acquired chronic cerebellar herniation. Nevertheless, positional plagiocephaly and Chiari-1 are common entities, and it is possible that the dual diagnoses were coincidental in this case. This report serves to raise awareness of a putative causal relationship between positional plagiocephaly, reduced posterior fossa volume, and hindbrain herniation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Listeria rhombencephalitis is a rare cause of brain stem encephalitis. We report a case with a history of immunosupressive therapy due to Takayasu's arteritis that was treated with corticosteroids and linezolid for Listeria rhombencephalitis. A 63-year-old woman was admitted to the hospital with fever, headache, nausea, and vomiting. The patient's body temperature was 38°C, and she had a stiff neck. Listeria monocytogenes was isolated from the cerebrospinal fluid (CSF), and penicillin G and gentamicin treatment was initiated. Linezolid and dexamethasone were added. Due to hematuria and thrombocytopenia, the linezolid was discontinued. In immunocompromised patients with CNS infections, Listeria rhombencephalitis should be suspected. Linezolid can be used in combination with dexamethasone., (Copyright © 2016 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.)