Cisterna Magna Research Articles

A Clinical Approach to Semiautomated Three-Dimensional Fetal Brain Biometry-Comparing the Strengths and Weaknesses of Two Diagnostic Tools: 5DCNS+TM and SonoCNSTM.

(1) Objective: We aimed to evaluate the accuracy and efficacy of AI-assisted biometric measurements of the fetal central nervous system (CNS) by comparing two semiautomatic postprocessing tools. We further aimed to discuss the additional value of semiautomatically generated sagittal and coronal planes of the CNS. (2) Methods: Three-dimensional (3D) volumes were analyzed with two semiautomatic software tools, 5DCNS+™ and SonoCNS™. The application of 5DCNS+™ results in nine planes (axial, coronal and sagittal) displayed in a single template; SonoCNS™ depicts three axial cutting sections. The tools were compared regarding automatic biometric measurement accuracy. (3) Results: A total of 129 fetuses were included for final analysis. Our data indicate that, in terms of the biometric quantification of head circumference (HC), biparietal diameter (BPD), transcerebellar diameter (TCD) and cisterna magna (CM), the accuracy of SonoCNS™ was higher with respect to the manual measurement of an experienced examiner compared to 5DCNS+™, whereas it was the other way around regarding the diameter of the posterior horn of the lateral ventricle (Vp). The inclusion of four orthogonal coronal views in 5DCNS+™ gives valuable information regarding spatial arrangements, particularly of midline structures. (4) Conclusions: Both tools were able to ease assessment of the intracranial anatomy, highlighting the additional value of automated algorithms in clinical use. SonoCNS™ showed a superior accuracy of plane reconstruction and biometry, but volume reconstruction using 5DCNS+™ provided more detailed information, which is needed for an entire neurosonogram as suggested by international guidelines.

Anatomical Implications of Chiari I and Basilar Invagination (Type B) in the IV Ventricle and Cisterna Magna

To analyze the anatomical changes of the IV ventricle and cisterna magna in the Chiari malformation I (CMI) and basilar invagination (type B). This is a controlled study with 161 exams of magnetic resonance imaging (MRI) of adults grouped into control (n= 37), basilar invagination (BI; n= 31), Chiari malformation I (CMI; n= 37), and CMI+BI (n= 56). The MRIs were analyzed using the visualization software Osirix (Pixmeo, Bernex, Geneva, version 3.8.2). The morphometric variables were: distance from the obex to the McRae line; length of the IV ventricle floor; and the area and volume of the cisterna magna. The univariate ANOVA followed by Tukey's post-hoc test was applied to evaluate the difference between the groups. The difference between sexes was evaluated by the t test for each group. Alterations in the cisterna magna and IV ventricle were more evident only in the CMI and CMI+BI groups. For both sexes, the CMI and CMI+BI groups showed: a reduction in the CSF space (P < 0.001), cisterna magna with volume reduction (P < 0.001), low position of the obex (P < 0.001), and IV ventricle more elongated (male P= 0.007 and female P < 0.001). The BI group had no significant change in the analysis by sex. The CMI (isolated and associated with BI) showed a low obex position and elongation of the IV ventricle due to traction towards the spinal canal. The reduction of cisterna magna volume added to the occupation of the cerebellar tonsils can impact in the cerebrospinal fluid dynamics. The BI when isolated was not related to alterations in the parameters of cerebrospinal fluid spaces studied.

Detailed Anatomy of Bridging Veins Around the Foramen Magnum: a Multicenter Study Using Three-dimensional Angiography

Background and PurposeThere has been limited literature regarding the bridging veins (BVs) of the medulla oblongata around the foramen magnum (FM). The present study aims to analyze the normal angioarchitecture of the BVs around the FM using slab MIP images of three-dimensional (3D) angiography.MethodsWe collected 3D angiography data of posterior fossa veins and analyzed the BVs around the FM using slab MIP images. We analyzed the course, outlet, and number of BVs around the FM. We also examined the detection rate and mean diameter of each BV.ResultsOf 57 patients, 55 patients (96%) had any BV. The median number of BVs was two (range: 0–5). The BVs originate from the perimedullary veins and run anterolaterally to join the anterior condylar vein (ACV), inferior petrosal sinus, sigmoid sinus, or jugular bulb, inferolaterally to join the suboccipital cavernous sinus (SCS), laterally or posterolaterally to join the marginal sinus (MS), and posteriorly to join the MS or occipital sinus. We classified BVs into five subtypes according to the draining location: ACV, jugular foramen (JF), MS, SCS, and cerebellomedullary cistern (CMC). ACV, JF, MS, SCS, and CMC BVs were detected in 11 (19%), 18 (32%), 32 (56%), 20 (35%), and 16 (28%) patients, respectively. The mean diameter of the BVs other than CMC was 0.6 mm, and that of CMC BV was 0.8 mm.ConclusionUsing venous data from 3D angiography, we detected FM BVs in most cases, and the BVs were connected in various directions.

Finding its place on the spectrum of pituitary duplication disorders, duplication of pituitary stalk: A case report with brief review of literature.

Pituitary gland duplication is a rare abnormality and isolated duplication of the pituitary stalk without any pituitary anomaly is an even rarer entity with this case being the first documented case till date. Although incidentally discovered cases of duplication of pituitary gland (DPG) have been reported, sometimes with a duplicated pituitary stalk, patients with this disorder usually present with other craniofacial abnormalities. Consequently, DPG plus syndrome is used as it is often accompanied by endocrine disturbances and pathologies such as median cleft face syndrome, ocular disorders, craniocervical bony abnormalities, vascular anomalies and tuberomammillary masses. Since this is the first reported case without any additional pituitary gland anomaly, we propose the acronym DPS (duplication of pituitary stalk) to be used to unify this entity as we are certain that much like the previously described pituitary duplication disorders, more cases will be documented independently rather than under the umbrella of pituitary duplication disorders. This is critical as the life expectancy (age of diagnosis) in the cases reviewed in our study is as good as normal population with no obvious increase in mortality as compared to existing pituitary duplication syndromes. We present a case report of a 2year 7month old girl who was referred by the paediatrician for evaluation of premature thelarche. The duplication of the pituitary stalk along with mega cisterna magna and tuberomammillary fusion was the only positive finding on imaging with the pituitary gland being absolutely normal.

A valuable subarachnoid space named the occipito-atlantal cistern

The cisterna magna has been defined as the space between the inferior margin of the cerebellar vermis to the level of the foramen magnum, while an enlarged dorsal subarachnoid space at the occipito-cervical junction extending from the foramen magnum to the upper border of the axis (C2) is still ignored. Recently, the myodural bridge complex is proved to drive the cerebral spinal fluid flowing via this region, we therefore introduce the “occipito-atlantal cistern (OAC)” to better describe the subarachnoid space and provide a detailed rationale. The present study utilized several methods, including MRI, gross anatomical dissection, P45 sheet plastination, and three-dimensional visualization. OAC was observed to be an enlarge subarachnoid space, extending from the foramen magnum to the level of the C2. In the median sagittal plane, OAC was a funnel shape and its anteroposterior dimensions were 15.92 ± 4.20 mm at the level of the C0, 4.49 ± 1.25 mm at the level of the posterior arch of the C1, and 2.88 ± 0.77 mm at the level of the arch of the C2, respectively. In the median sagittal plane, the spino-dural angle of the OAC was calculated to be 35.10 ± 6.91°, and the area of OAC was calculated to be 232.28 ± 71.02 mm2. The present study provides OAC is a subarachnoid space independent from the cisterna magna. Because of its distinctive anatomy, as well as theoretical and clinical significance, OAC deserves its own name.

Effect of isolated intracranial hypertension on cerebral perfusion within the phase of primary disturbances after subarachnoid hemorrhage in rats.

Elevated intracranial pressure (ICP) and blood components are the main trigger factors starting the complex pathophysiological cascade following subarachnoid hemorrhage (SAH). It is not clear whether they independently contribute to tissue damage or whether their impact cannot be differentiated from each other. We here aimed to establish a rat intracranial hypertension model that allows distinguishing the effects of these two factors and investigating the relationship between elevated ICP and hypoperfusion very early after SAH. Blood or four different types of fluids [gelofusine, silicone oil, artificial cerebrospinal fluid (aCSF), aCSF plus xanthan (CX)] were injected into the cisterna magna in anesthetized rats, respectively. Arterial blood pressure, ICP and cerebral blood flow (CBF) were continuously measured up to 6 h after injection. Enzyme-linked immunosorbent assays were performed to measure the pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) in brain cortex and peripheral blood. Silicone oil injection caused deaths of almost all animals. Compared to blood, gelofusine resulted in lower peak ICP and lower plateau phase. Artificial CSF reached a comparable ICP peak value but failed to reach the ICP plateau of blood injection. Injection of CX with comparable viscosity as blood reproduced the ICP course of the blood injection group. Compared with the CBF course after blood injection, CX induced a comparable early global ischemia within the first minutes which was followed by a prompt return to baseline level with no further hypoperfusion despite an equal ICP course. The inflammatory response within the tissue did not differ between blood or blood-substitute injection. The systemic inflammation was significantly more pronounced in the CX injection group compared with the other fluids including blood. By cisterna magna injection of blood substitution fluids, we established a subarachnoid space occupying rat model that exactly mimicked the course of ICP in the first 6 h following blood injection. Fluids lacking blood components did not induce the typical prolonged hypoperfusion occurring after blood-injection in this very early phase. Our study strongly suggests that blood components rather than elevated ICP play an important role for early hypoperfusion events in SAH.

Durative sleep fragmentation with or without hypertension suppress rapid eye movement sleep and generate cerebrovascular dysfunction

Either hypertension or chronic insomnia is the risk factor of developing vascular dementia. Durative hypertension can induce vascular remodeling and is used for modeling small vessel disease in rodents. It remains undetermined if the combination of hypertension and sleep disturbance exacerbates vascular dysfunction or pathologies. Previously, we found chronic sleep fragmentation (SF) dampened cognition in young mice without disease predispositions. In the current study, we superimposed SF with hypertension modeling in young mice. Angiotensin II (AngII)-releasing osmotic mini pumps were subcutaneously implanted to generate persistent hypertension, while sham surgeries were performed as controls. Sleep fragmentation with repetitive arousals (10 s every 2 min) during light-on 12 h for consecutive 30 days, while mice undergoing normal sleep (NS) processes were set as controls. Sleep architectures, whisker-stimulated cerebral blood flow (CBF) changes, vascular responsiveness as well as vascular pathologies were compared among normal sleep plus sham (NS + sham), SF plus sham (SF + sham), normal sleep plus AngII (NS + AngII), and SF plus AngII (SF + AngII) groups. SF and hypertension both alter sleep structures, particularly suppressing REM sleep. SF no matter if combined with hypertension strongly suppressed whisker-stimulated CBF increase, suggesting the tight association with cognitive decline. Hypertension modeling sensitizes vascular responsiveness toward a vasoactive agent, Acetylcholine (ACh, 5 mg/ml, 10 μl) delivered via cisterna magna infusion, while SF exhibits a similar but much milder effect. None of the modeling above was sufficient to induce arterial or arteriole vascular remodeling, but SF or SF plus hypertension increased vascular network density constructed by all categories of cerebral vessels. The current study would potentially help understand the pathogenesis of vascular dementia, and the interconnection between sleep and vascular health.

CSF - injected contrast medium enhances post-traumatic spinal cord cysts. An experimental study in rats.

Spinal cord injury (SCI) is still one of the most challenging problems in neurosurgical practice. One of the major obstacles to neural regeneration following trauma is the formation of glial scarring and post-traumatic cysts which acts against proper growth of axons through the site of injury. Cerebrospinal fluid (CSF) delivery of bioactive agents into cystic cavities could represent a promising therapeutic strategy. In the present study, we investigated specifically the dynamics of intradural delivery of contrast medium and its relocation into post-traumatic cysts in an experimental model of spinal cord cryoinjury in rats. 32 male Sprague Dawley SPF rats were submitted to injury as previously described. Omnipaque-240 was injected either into the cisterna magna or at the level of the cauda equina. Subsequently, cerebral CT scan examinations were performed in order to check the CSF dynamics of the contrast medium. There was a steady accumulation of contrast medium into post-traumatic cysts as early as five minutes after injection. A dosage of 65 mg of iodine per kilogram ensured an adequate feeling of the cysts at an average of 30 minutes. Our data indicate that intraspinal injection of bioactive agents can easily reach the site of injury and fill post-traumatic cysts. This could represent an interesting potential therapeutic protocol for SCI.

Detection of Leptomeningeal Carcinomatosis by Cerebrospinal Fluid in a Dog with a Negative MRI

ABSTRACT An 11 yr old female French bulldog was presented for acute onset of seizures and a 2 wk history of disorientation. On physical examination, a nodular mass at the fourth mammary gland level was observed. Neurological evaluation showed obtundation and compulsive behavior. Brain MRI study did not reveal any abnormalities. Cerebrospinal fluid (CSF) collected from the cerebellomedullary cistern showed a marked increase of total nucleated cell count (400 cells/μL). Cytological evaluation identified the presence of a monomorphic round cell population characterized by large cell bodies, a single eccentrical located nucleus with high nuclear:cytoplasmatic ratio, and marked atypia with anisocytosis, anisokaryosis, and multiple nucleoli. Leptomeningeal carcinomatosis (LC) was suspected. The dog was euthanatized for worsening of clinical signs. Post-mortem examination identified an anaplastic mammary carcinoma in the nodular mammary mass. Infiltration by neoplastic cells exhibiting the same morphological features was detected along leptomeninges of the telencephalon and cerebellum associated with cortical and subcortical parenchymal micrometastases. To our knowledge, this is the first case of LC in a dog detected by CSF evaluation but without any MRI abnormalities. This finding emphasizes the usefulness of CSF cytology in patients with suspected LC even in the absence of any MRI identifiable lesions.

Standardizing an Experimental Murine Model of Extraparenchymal Neurocysticercosis That Immunologically Resembles Human Infection.

Neurocysticercosis (NCC) is endemic in non-developed regions of the world. Two forms of NCC have been described, for which neurological morbidity depends on the location of the lesion, which can be either within the cerebral parenchyma or in extraparenchymal spaces. The extraparenchymal form (EXP-NCC) is considered the most severe form of NCC. EXP-NCC often requires several cycles of cysticidal treatment and the concomitant use of glucocorticoids to prevent increased inflammation, which could lead to intracranial hypertension and, in rare cases, to death. Thus, the improvement of EXP-NCC treatment is greatly needed. An experimental murine model of EXP-NCC, as an adequate model to evaluate new therapeutic approaches, and the parameters that support it are described. EXP-NCC was established by injecting 30 Taenia crassiceps cysticerci, which are less than 0.5 mm in diameter, into the cisterna magna of male and female Wistar rats. Cyst implantation and infection progression were monitored by detecting the HP10 antigen and anti-cysticercal antibodies in the serum and cerebral spinal fluid (CSF) of infected rats and by magnetic resonance imaging. Higher HP10 levels were observed in CSF than in the sera, as in the case of human EXP-NCC. Low cell recruitment levels were observed surrounding established cysticerci in histological analysis, with a modest increase in GFAP and Iba1 expression in the parenchyma of female animals. Low cellularity in CSF and low levels of C-reactive protein are consistent with a weak inflammatory response to this infection. After 150 days of infection, EXP-NCC is accompanied by reduced levels of mononuclear cell proliferation, resembling the human disease. EXP-NCC does not affect the behavior or general status of the rats. This model will allow the evaluation of new approaches to control neuroinflammation and immunomodulatory treatments to restore and improve the specific anti-cysticercal immunity in EXP-NCC.

MicroRNA-130b May Induce Cerebral Vasospasm after Subarachnoid Hemorrhage via Modulating Kruppel-like Factor 4.

Recently, the diverse functions of microRNAs (miRNAs) in brain diseases have been demonstrated. We intended to uncover the functional role of microRNA-130b (miR-130b) in cerebral vasospasm (CVS) following subarachnoid hemorrhage (SAH). SAH was induced by injecting the autologous blood into the cisterna magna of Sprague Dawley rats. The cerebral vascular smooth muscle cells (cVSMCs) were extracted for invitro experimentation. In vitro and invivo assays were implemented with transfection of miR-130b mimic/inhibitor, sh-Kruppel-like factor 4 (KLF4), oe-KLF4 plasmids or p38/MAPK signaling pathway agonist (anisomycin), respectively, to elaborate the role of miR-130b in CVS following SAH. Elevated miR-130b and reduced KLF4 were found in SAH patients and rat models of SAH. KLF4 was the target gene of miR-130b. miR-130b promoted the proliferation and migration of cVSMCs through the Inhibition of KLF4. Besides, KLF4 inhibited the proliferation and migration of cVSMCs through blockage of the p38/MAPK pathway. Furthermore, invivo assay confirmed the inhibitory effect of decreased miR-130b in CVS following SAH. In conclusion, miR-130b may activate the p38/MAPK signaling pathway through targeted inhibition of KLF4, thereby contributing to some extent to the development of cerebral vasospasm after SAH.

Effect of Ginseng Extract Ginsenoside Rg1 on Mice with Intracerebral Injury

Background: Traditional Chinese medicine has a long history of treating intracerebral injury. The aim of this research is to test the hypothesis that Ginsenoside Rg1 can alleviate brain injury in subarachnoid hemorrhage (SAH) mice. Methods: SAH mice were induced by autologous blood injection into cisterna magna, the mortality and neurological function were assessed. Ginsenoside Rg1 was administered continuously for seven days after SAH. Then, Y-maze test was used to detect the neurological deficits. Brains were harvested to evaluate the neuroinflammation of SAH by immunofluorescence staining and flow cytometry. Cerebral vasospasm was evaluated by hematoxylin-eosin (HE) staining, and neuronal apoptosis was evaluated by TdT-mediated dUTP Nick-End Labeling (TUNEL) staining and HE staining. Results: We demonstrate that Ginsenoside Rg1 reduced mortality and improved neurological deficits, reduced inflammatory response, ameliorated cerebral vasospasm and neuronal apoptosis after SAH. Conclusion: Ginsenoside Rg1 can alleviate brain damage after SAH in mice.

GABA promotes interstitial fluid clearance in an AQP4-dependent manner by activating the GABAA R.

The glymphatic system is a newly discovered perivascular network where cerebrospinal fluid mixes with interstitial fluid, facilitating clearance of protein solutes and metabolic waste from the parenchyma. The process is strictly dependent on water channel aquaporin-4 (AQP4) expressed on the perivascular astrocytic end-feet. Various factors, such as noradrenaline levels related to the arousal state, influence clearance efficiency, highlighting the possibility that other neurotransmitters additionally modulate this process. To date, the specific role of γ-aminobutyric acid (GABA) in the glymphatic system remains unknown. We used C57BL/6J mice to observe the regulatory effect of GABA on glymphatic pathway by administering a cerebrospinal fluid tracer containing GABA or its GABAA receptor (GABAA R) antagonist through cisterna magna injection. Then, we employed an AQP4 knockout mouse model to explore the regulatory effects of GABA on glymphatic drainage and further study whether transcranial magnetic stimulation-continuous theta burst stimulation (cTBS) could regulate the glymphatic pathway through the GABA system. Our data showed that GABA promotes glymphatic clearance in an AQP4-dependent manner by activating the GABAA R. Furthermore, cTBS was found to modulate the glymphatic pathway by activating the GABA system. Accordingly, we propose that regulating the GABA system by cTBS could modulate glymphatic clearance and provide new insight for clinical prevention and treatment of abnormal protein deposition-related diseases.

E2511, a novel small compound TrkA biased positive allosteric modulator, reinnervates cholinergic neuron and activates cholinergic functions in non‐clinical studies

AbstractBackgroundCholinergic innervation is particularly vulnerable in many neurodegenerative diseases associated with cognitive dysfunction, and loss of cholinergic neurons in Alzheimer’s disease (AD) is pathogenic event observed from early stage correlated with cognitive impairment. Nerve growth factor (NGF) plays a major role in the maintenance and function of cholinergic neurons, and a decrease in trophic signalling by NGF‐Tropomyosin receptor kinase A (TrkA) contributes to cholinergic neurodegeneration and cognitive decline during the course of AD. The activation of NGF‐induced trophic signal could be a promising therapy for the neurodegenerative diseases including AD, reinnervating and maintaining cholinergic neurons to functional status. E2511 was identified as a novel small compound TrkA biased positive allosteric modulator that can enhance specific trophic signal of NGF signal without induction of NGF‐like adverse effect via direct binding to TrkA in primary neuron culture and animal model. We present evidence that E2511 induced functional restoration of cholinergic neuron in animal model and rats.MethodThe trophic effect of E2511 on cholinergic neurons was assessed by biochemical studies such as western blotting and immunohistochemistry in human Tau P301S transgenic mice (Tau tg mice) following once‐daily oral administrations of E2511 for 3 months. E2511 TrkA downstream trophic effects on acetylcholine (ACh) were evaluated in cerebrospinal fluid (CSF) collected from cisterna magna in normal SD rats treated with once‐daily oral E2511 for 14 days, using an original LCMS method.ResultChronic administration of E2511 demonstrated reinnervative effects on cholinergic presynapses as well as a correlation with improvement of the number of cholinergic neurons in Tau tg mice. In SD rats, CSF ACh increased in a dose‐dependent manner at exposures associated with cholinergic reinnervation, with changes also correlating with increases in choline acetyltransferase mRNA level. These results suggest that CSF ACh may be a useful marker to establish the E2511 effective dose in humans.ConclusionE2511 functionally reinnervates cholinergic neuronal network in the Tau tg mice. CSF ACh increased in a dose‐related manner in SD rats. CSF ACh may be used as a pharmacodynamic marker to establish the dose showing the reinnervative effect of E2511 in clinical studies.

A Minimally-Invasive Method for Serial Cerebrospinal Fluid Collection and Injection in Rodents with High Survival Rates.

Cerebrospinal fluid (CSF) is an important sample source for diagnosing diseases in the central nervous system (CNS), but collecting and injecting CSF in small animals is technically challenging and often results in high mortality rates. Here, we present a cost-effective and efficient method for accessing the CSF in live rodents for fluid collection and infusion purposes. The key element of this protocol is a metal needle tool bent at a unique angle and length, allowing the successful access of the CSF through the foramen magnum. With this method, we can collect 5-10 µL of the CSF from mice and 70-100 µL from rats for downstream analyses, including mass spectrometry. Moreover, our minimally-invasive procedure enables iterative CSF collection from the same animal every few days, representing a significant improvement over prior protocols. Additionally, our method can be used to inject solutions into mice cisterna magna with high success rates and high postoperative recovery rates. In summary, we provide an efficient and minimally-invasive protocol for collecting and infusing reagents into the CSF in live rodents. We envision this protocol will facilitate biomarker discovery and drug development for diseases in the central nervous system.

Semilobar Holoprosencephaly Caused by a Novel and De Novo ZIC2 Pathogenic Variant.

Holoprosencephaly (HPE) is the most common embryonic forebrain developmental anomaly. It involves incomplete or absent division of the prosencephalon into two distinct cerebral hemispheres during the early stages of organogenesis. HPE is etiologically heterogeneous, and its clinical presentation is very variable. We report a case of a 7 month old female infant, diagnosed with non-syndromic semilobar holoprosencephaly, caused by a novel, de novo pathogenic variant in ZIC2 - one of the most commonly mutated genes in non-syndromic HPE coding for the ZIC2 transcription factor. The patient presented with microcephaly, mild facial dysmorphic features, central hypotonia and spasticity on all four extremities. Ultrasound imaging demonstrated the absence of septum pellucidum, semilobar fusion of the hemispheres and mega cisterna magna and brain MRI with confirmed the diagnosis of HPE. Early diagnosis and management are important for the prevention and treatment of complications associated with this condition.

Open pathways for cerebrospinal fluid outflow at the cribriform plate along the olfactory nerves

Routes along the olfactory nerves crossing the cribriform plate that extend to lymphatic vessels within the nasal cavity have been identified as a critical cerebrospinal fluid (CSF) outflow pathway. However, it is still unclear how the efflux pathways along the nerves connect to lymphatic vessels or if any functional barriers are present at this site. The aim of this study was to anatomically define the connections between the subarachnoid space and the lymphatic system at the cribriform plate in mice. PEGylated fluorescent microbeads were infused into the CSF space in Prox1-GFP reporter mice and decalcification histology was utilized to investigate the anatomical connections between the subarachnoid space and the lymphatic vessels in the nasal submucosa. A fluorescently-labelled antibody marking vascular endothelium was injected into the cisterna magna to demonstrate the functionality of the lymphatic vessels in the olfactory region. Finally, we performed immunostaining to study the distribution of the arachnoid barrier at the cribriform plate region. We identified that there are open and direct connections from the subarachnoid space to lymphatic vessels enwrapping the olfactory nerves as they cross the cribriform plate towards the nasal submucosa. Furthermore, lymphatic vessels adjacent to the olfactory bulbs form a continuous network that is functionally connected to lymphatics in the nasal submucosa. Immunostainings revealed a discontinuous distribution of the arachnoid barrier at the olfactory region of the mouse. Our data supports a direct bulk flow mechanism through the cribriform plate allowing CSF drainage into nasal submucosal lymphatics in mice. This study was supported by the Swiss National Science Foundation (310030_189226), Dementia Research Switzerland-Synapsis Foundation, the Heidi Seiler Stiftung and the Fondation Dr. Corinne Schuler.

Long-Term Outcome of Neonatal Seizure with PACS2 Mutation: Case Series and Literature Review.

Phosphofurin Acidic Cluster Sorting Protein 2 (PACS2)-related early infantile developmental and epileptic encephalopathy (EIDEE) is a rare neurodevelopmental disorder. EIDEE is characterized by seizures that begin during the first three months of life and are accompanied by developmental impairment over time. In this article, we present three patients with EIDEE who experienced neonatal-onset seizures that developed into intractable seizures during infancy. Whole exome sequencing revealed a de novo heterozygous missense variant in all three patients in the p.Glu209Lys variant of the PACS2 gene. We conducted a literature review and found 29 cases to characterize the seizure patterns, neuroimaging features, the usage of anticonvulsants, and the clinical neurodevelopmental outcomes of PACS2-related EIDEE. The seizures were characterized by brief, recurring tonic seizures in the upper limbs, sometimes accompanied by autonomic features. Neuroimaging abnormalities were observed in the posterior fossa region, including mega cisterna magna, cerebellar dysplasia, and vermian hypoplasia. The long-term prognosis ranges from low-average intelligence to severe developmental retardation, emphasizing the importance of early recognition and accurate diagnosis by pediatric neurologists to provide personalized patient management.

Bilirubin induces microglial NLRP3 inflammasome activation in vitro and in vivo

Despite current advancements in neonatal care, hyperbilirubinemia resulting in bilirubin-induced neurological dysfunction (BIND) continues to be one of the major reasons of mortality or lifelong disability. Although the exact mechanisms underlying brain injury upon bilirubin exposure remains unelucidated, inflammation is considered to be one of the major contributors to BIND. This study investigates the role of the NLRP3 inflammasome in bilirubin-induced injury using in vitro and in vivo models. We successfully demonstrated that the upregulation of NLRP3 expression is significantly associated with the release of active caspase-1 and IL-1β in N9 microglial cells exposed to bilirubin. Functional in vitro experiments with NLRP3 siRNA confirms that bilirubin-induced inflammasome activation and cell death are mediated by the NLRP3 inflammasome. Following injection of bilirubin into the cisterna magna of a neonatal mouse, activation of the NLRP3 inflammasome and microglia were determined by double staining with Iba1-NLRP3 and Iba1-Caspase-1. Upon injection of bilirubin into the cisterna magna, neuronal loss was significantly higher in the wild-type mouse compared to Nlrp3−/− and Caspase-1−/− strains. Collectively, these data indicate that NLRP3 inflammasome has a crucial role in microglial activation and bilirubin-induced neuronal damage.

Cisterna Magna Injection Mouse Model of Subarachnoid Hemorrhage (SAH): A Systematic Literature Review of Preclinical SAH Research

Objective: This review article describes the characteristics of published literature using the cisterna magna blood injection mouse model of subarachnoid hemorrhage (SAH) with the aim to define particular standards and identify moderators of mortality rate, SAH grade, and large artery vasospasm. Methods: We searched for English-original peer-reviewed studies which reported the induction of SAH in mice via single or multiple blood injections into the cisterna magna. The search included studies published until 13th February 2023 on PubMed, Embase and Web of Science. Furthermore, we investigated the reporting of mortality rate, vasospasms by measuring large arteries, and SAH grade in cisterna magna blood injection mouse model. Results: Seven articles out of 136 identified records matched our inclusion criteria and were therefore included in descriptive analysis. Four articles reported the mortality rate which varied between zero and 22 percent. Five articles displayed vasospasms of large cerebral arteries including basilar artery (BA), anterior cerebral artery (ACA), and middle cerebral artery (MCA). Interestingly, the diameters of the observed arteries started to decrease already within the first hour after blood injection and achieved the lowest values at different times, but mainly between six and twelve hours after SAH induction. The artery diameters reached nearly their pre-SAH (control group) diameters approximately after four to seven days after SAH. However, the SAH severity grade was reported in none of these publications. No uniform model characteristics were observed in current literature. Conclusion: A systemic overview of the cisterna magna blood injection mouse model of SAH is presented. An important heterogeneity was observed. Hence, standardized model features and study endpoints have to be defined in order to improve reporting frequency and quality to enhance the reproducibility of preclinical SAH research in the future.