Intracranial Compartment Research Articles

Human in-vivo magnetic resonance current density imaging of the brain by optimizing head tissue conductivities

Abstract Introduction: Magnetic resonance current density imaging (MRCDI) aims to reconstruct the current flow of transcranial electrical stimulation (TES) in the brain from MR-measurements of the current-induced magnetic field Bz. Aim: We test the performance of a standard reconstruction algorithm (“projected current density algorithm”, PCD, Jeong et al. 2014) for human brain data. We compare it with current flow simulations using personalized head models. Methods:1. We generated ground-truth data for the TES current flow and Bz-field using a detailed head model and SimNIBS (www.simnibs.org). We applied the PCD algorithm to the Bz -field and quantified the reconstruction performance by comparison with the ground-truth current flow. We additionally compared the PCD results with simulations using a simple head model (“3c” with scalp, bone and a homogeneous intracranial compartment). 2. We reconstructed the current flow from in-vivo MRCDI data (Göksu et al, 2018) with the PCD algorithm. We also used head models of different complexities (“3c” and “4c”: scalp, skull, CSF & brain) and optimized their conductivities to minimize the root-mean-square difference between the measured and simulated Bz. Results: 1. For simulated Bz data, the PCD algorithm only coarsely reconstructed the true current flow. Even the simple head model performed better. 2. For measured Bz data, current flows obtained with personalized head models and fitted conductivities explained the measurements better than the current flow reconstructed with the PCD algorithm. This was already the case for the simple head model (3c). The more detailed model (4c) resulted in further statistically significant improvements. However, for all models, the unexplained variance stayed above the noise floor, indicating remaining differences to unknown true current flow. Conclusions: The PCD algorithm has low accuracy for MRCDI data of the brain. However, MRCDI is useful for evaluations and improvements of current flow simulations with anatomically detailed personalized head models. Keywords: magnetic resonance current density imaging, personalized electric field calculation, dose control, transcranial electrical stimulation

Intracranial Compliance Concepts and Assessment: A Scoping Review.

Background: Intracranial compliance (ICC) has been studied to complement the interpretation of intracranial pressure (ICP) in neurocritical care and help predict brain function deterioration. It has been reported that ICC is related to maintaining ICP stability despite changes in intracranial volume. However, this has not been properly translated to clinical practice. Therefore, the main objective of this scoping review was to map the key concepts of ICC in the literature. This review also aimed to characterize the relationship between ICC and ICP and systematically describe the outcomes used to assess ICC using both invasive and non-invasive measurement methods.Methods: This review included the following: (1) population: animal and humans, (2) concept of compliance or its inverse “elastance,” and (3) context: neurocritical care. Therefore, literature searches without a time frame were conducted on several databases using a combination of keywords and descriptors.Results and Discussion: 43,339 articles were identified, and 297 studies fulfilled the inclusion criteria after the selection process. One hundred and five studies defined ICC. The concept was organized into three main components: physiological definition, clinical interpretation, and localization of the phenomena. Most of the studies reported the concept of compliance related to variations in volume and pressure or its inverse (elastance), primarily in the intracranial compartment. In addition, terms like “accommodation,” “compensation,” “reserve capacity,” and “buffering ability” were used to describe the clinical interpretation. The second part of this review describes the techniques (invasive and non-invasive) and outcomes used to measure ICC. A total of 297 studies were included. The most common method used was invasive, representing 57–88% of the studies. The most commonly assessed variables were related to ICP, especially the absolute values or pulse amplitude. ICP waveforms should be better explored, along with the potential of non-invasive methods once the different aspects of ICC can be measured.Conclusion: ICC monitoring could be considered a complementary resource for ICP monitoring and clinical examination. The combination and validation of invasive/non-invasive or non-invasive measurement methods are required.

Interactions of brain, blood, and CSF: a novel mathematical model of cerebral edema

BackgroundPrevious models of intracranial pressure (ICP) dynamics have not included flow of cerebral interstitial fluid (ISF) and changes in resistance to its flow when brain swelling occurs. We sought to develop a mathematical model that incorporates resistance to the bulk flow of cerebral ISF to better simulate the physiological changes that occur in pathologies in which brain swelling predominates and to assess the model’s ability to depict changes in cerebral physiology associated with cerebral edema.MethodsWe developed a lumped parameter model which includes a representation of cerebral ISF flow within brain tissue and its interactions with CSF flow and cerebral blood flow (CBF). The model is based on an electrical analog circuit with four intracranial compartments: the (1) subarachnoid space, (2) brain, (3) ventricles, (4) cerebral vasculature and the extracranial spinal thecal sac. We determined changes in pressure and volume within cerebral compartments at steady-state and simulated physiological perturbations including rapid injection of fluid into the intracranial space, hyperventilation, and hypoventilation. We simulated changes in resistance to flow or absorption of CSF and cerebral ISF to model hydrocephalus, cerebral edema, and to simulate disruption of the blood–brain barrier (BBB).ResultsThe model accurately replicates well-accepted features of intracranial physiology including the exponential-like pressure–volume curve with rapid fluid injection, increased ICP pulse pressure with rising ICP, hydrocephalus resulting from increased resistance to CSF outflow, and changes associated with hyperventilation and hypoventilation. Importantly, modeling cerebral edema with increased resistance to cerebral ISF flow mimics key features of brain swelling including elevated ICP, increased brain volume, markedly reduced ventricular volume, and a contracted subarachnoid space. Similarly, a decreased resistance to flow of fluid across the BBB leads to an exponential-like rise in ICP and ventricular collapse.ConclusionsThe model accurately depicts the complex interactions that occur between pressure, volume, and resistances to flow in the different intracranial compartments under specific pathophysiological conditions. In modelling resistance to bulk flow of cerebral ISF, it may serve as a platform for improved modelling of cerebral edema and blood–brain barrier disruption that occur following brain injury.

Recurrent Olfactory Groove Meningioma Filling the Nasal Cavity: A Case Report and Technical Video

Abstract Background Meningiomas are usually benign tumors and account for 15% of the overall intracranial tumors. Less than 3% of them extend up to the sinonasal region. Case Report A 61-year-old woman, operated on for a huge olfactory meningioma 8 years before, came for progressive nasal obstruction. On physical examination, a mass that completely obliterated the right nasal passage was detected. A c.e. cranial MRI confirmed the presence of an enhancing mass completely occupying the right nostril, without intracranial extension. A biopsy of the mass revealed a meningioma (WHO grade I) and the patient was admitted to our department for the surgical removal of the endonasal recurrent tumor. Results The meningioma was approached and excised by endonasal endoscopic approach using a microdebrider and electrocautery. A linear residual of tumor was left attached to the previous anterior skull base’ vascularized galeal flap, in order to avoid a communication with the intracranial compartment and a possible cerebrospinal fluid (CSF) leak. The postoperative course was uneventful, and the patient immediately referred an improvement in breathing. A c.e. postoperative MRI confirmed the nearly total removal of tumor. Conclusions We present a video with the most relevant steps of transnasal endoscopic surgical removal of a quite rare case of a recurrent olfactory groove meningioma, completely obliterating the right nostril.

Cerebrospinal fluid (CSF) analysis and role in clinical neurology

Cerebrospinal fluid (CSF) is a clear fluid coursing in the intracranial and spinal compartments. By estimating the levels of various CSF components utilizing relevant techniques, diagnosis, severity and prognostication of neurological conditions like infections, subarachnoid hemorrhage, demyelinating conditions, tumor like conditions, etc. can be done.Cerebrospinal fluid (CSF) provides an extremely valuable matrix for biomarker research for several purposes such as diagnosis, prognosis monitoring and identification of prominent leads in pathways of neurological disease.

OMRT-9. Effect of Pre-Operative Stereotactic Radiosurgery on Brain Metastasis: Analysis of DNA and RNA Genomic Profiles from Phase-II Clinical Trial NCT03398694

BackgroundWith improved systemic therapy that has limited impact on the intracranial compartment, the incidence of brain metastasis (BM) from solid cancers is rising and negatively impacting patient’s overall survival (OS). Treatment varies based on presentation, however, for patients with <4 symptomatic BMs current clinical practice involves surgical resection followed by stereotactic radiosurgery (SRS) to the resection cavity. Post-operative SRS is associated with increased risk of leptomeningeal disease (LMD) and local recurrence in the follow-up period. We hypothesize that pre-operative SRS will decrease the incidence of LMD as well as local recurrence and increase patient’s OS by delivering a lethal dose of radiation to tumor cells before they are disturbed by surgical resection. In a Phase II clinical trial (NCT03398694) we are treating patients with 1–4 symptomatic BMs with pre-operative SRS while collecting DNA and RNA sequencing data from core and peripheral edges of the resected tumor to examine the genomic effects of SRS on tumor.MethodsPost-SRS resected tumor specimens were divided into two groups: ‘center’ and ‘periphery’ with respect to the center of SRS treatment with periphery within 50% isodose line. Previously resected untreated BMs were used as control. DNA and RNA were isolated from all samples for sequencing.ConclusionsOur initial analyses show that pre-treatment with SRS, results in significant genomic changes at DNA and RNA levels throughout the tumor, in both center as well as periphery. Furthermore, significant transcriptomic differences were noted among matched samples between the central and peripheral SRS locations implicating differential effect of SRS dosing within a tumor. Initial gene ontological analysis on non-small cell lung cancer samples demonstrated an overexpression of WNT and BMP signaling pathways (p <.001, p<.01). These pathways are typically involved in neuronal development, hinting that adaptation to the brain microenvironment was occurring post SRS treatment.

A proposed framework for cerebral venous congestion.

While venous congestion in the peripheral vasculature has been described and accepted, intracranial venous congestion remains poorly understood. The characteristics, pathophysiology, and management of cerebral venous stasis, venous hypertension and venous congestion remain controversial, and a unifying conceptual schema is absent. The cerebral venous and lymphatic systems are part of a complex and dynamic interaction between the intracranial compartments, with interplay between the parenchyma, veins, arteries, cerebrospinal fluid, and recently characterized lymphatic-like systems in the brain. Each component contributes towards intracranial pressure, occupying space within the fixed calvarial volume. This article proposes a framework to consider conditions resulting in brain and neck venous congestion, and seeks to expedite further study of cerebral venous diagnoses, mechanisms, symptomatology, and treatments. A multi-institution retrospective review was performed to identify unique patient cases, complemented with a published case series to assess a spectrum of disease states with components of venous congestion affecting the brain. These diseases were organized according to anatomical location and purported mechanisms. Outcomes of treatments were also analyzed. Illustrative cases were identified in the venous treatment databases of the authors. This framework is the first clinically structured description of venous pathologies resulting in intracranial venous and cerebrospinal fluid hypertension. Our proposed system highlights unique clinical symptoms and features critical for appropriate diagnostic work-up and potential treatment. This novel schema allows clinicians effectively to approach cases of intracranial hypertension secondary to venous etiologies, and furthermore provides a framework by which researchers can better understand this developing area of cerebrovascular disease.

Glioma-Specific Diffusion Signature in Diffusion Kurtosis Imaging.

Purpose: This study aimed to assess the relationship between mean kurtosis (MK) and mean diffusivity (MD) values from whole-brain diffusion kurtosis imaging (DKI) parametric maps in preoperative magnetic resonance (MR) images from 2016 World Health Organization Classification of Tumors of the Central Nervous System integrated glioma groups. Methods: Seventy-seven patients with histopathologically confirmed treatment-naïve glioma were retrospectively assessed between 1 August 2013 and 30 October 2017. The area on scatter plots with a specific combination of MK and MD values, not occurring in the healthy brain, was labeled, and the corresponding voxels were visualized on the fluid-attenuated inversion recovery (FLAIR) images. Reversely, the labeled voxels were compared to those of the manually segmented tumor volume, and the Dice similarity coefficient was used to investigate their spatial overlap. Results: A specific combination of MK and MD values in whole-brain DKI maps, visualized on a two-dimensional scatter plot, exclusively occurs in glioma tissue including the perifocal infiltrative zone and is absent in tissue of the normal brain or from other intracranial compartments. Conclusions: A unique diffusion signature with a specific combination of MK and MD values from whole-brain DKI can identify diffuse glioma without any previous segmentation. This feature might influence artificial intelligence algorithms for automatic tumor segmentation and provide new aspects of tumor heterogeneity.

Vanishing traumatic pneumocephalus – An alarm bell for the surgeon

Pneumocephalus usually occurs because of a bony defect between the intracranial compartments and the paranasal sinus. We present a case of traumatic non tension pneumocephalus with accompanying subdural haemorrhage (SDH) and fractures of the roof of sphenoid sinus.We noticed complete resolution of pneumocephalus with in a day on repeat CT head done on the next day. Significant resolution of SDH was also noted. This was unexpected as usually it takes 2-3 weeks for the complete resolution of non tension pneumocephalus. We assume that fracture in the roof of sphenoid sinus lead to CSF and haemorrhagic leakage through the sphenoethmoidal recess located within the superior meatus. This was unusual as CSF leakage is itself a cause of development of pneumocephalus when intracranial pressure is expected to increases, according to Ball Valve theory. So, the resolution of pneumocephalus was before the development of sufficient intracranial pressure to cause Ball valve effect. Hence, a complete resolution of a significant pneumocephalus and prompt regression of SDH in head injuries, with in few hours, should raise an alarm to exclude the possible association of CSF rhinorrhoea. Keywords: Pneumocephalus, CSF rhinorrhea, Subdural haemorrhage, Sphenoid roof fracture.

Cerebral venous steal equation for intracranial segmental perfusion pressure predicts and\xa0quantifies reversible\xa0intracranial to extracranial flow diversion

Cerebral perfusion is determined by segmental perfusion pressure for the intracranial compartment (SPP), which is lower than cerebral perfusion pressure (CPP) because of extracranial stenosis. We used the Thevenin model of Starling resistors to represent the intra-extra-cranial compartments, with outflow pressures ICP and Pe, to express SPP = Pd–ICP = FFR*CPP–Ge(1 − FFR)(ICP–Pe). Here Pd is intracranial inflow pressure in the circle of Willis, ICP—intracranial pressure; FFR = Pd/Pa is fractional flow reserve (Pd scaled to the systemic pressure Pa), Ge—relative extracranial conductance. The second term (cerebral venous steal) decreases SPP when FFR < 1 and ICP > Pe. We verified the SPP equation in a bench of fluid flow through the collapsible tubes. We estimated Pd, measuring pressure in the intra-extracranial collateral (supraorbital artery) in a volunteer. To manipulate extracranial outflow pressure Pe, we inflated the infraorbital cuff, which led to the Pd increase and directional Doppler flow signal reversal in the supraorbital artery. SPP equation accounts for the hemodynamic effect of inflow stenosis and intra-extracranial flow diversion, and is a more precise perfusion pressure target than CPP for the intracranial compartment. Manipulation of intra-extracranial pressure gradient ICP–Pe can augment intracranial inflow pressure (Pd) and reverse intra-extracranial steal.

Diagnostic Pathology of Tumors of Peripheral Nerve.

Neoplasms of the peripheral nervous system represent a heterogenous group with a wide spectrum of morphological features and biological potential. They range from benign and curable by complete excision (schwannoma and soft tissue perineurioma) to benign but potentially aggressive at the local level (plexiform neurofibroma) to the highly malignant (malignant peripheral nerve sheath tumors [MPNST]). In this review, we discuss the diagnostic and pathologic features of common peripheral nerve sheath tumors, particularly those that may be encountered in the intracranial compartment or in the spine and paraspinal region. The discussion will cover schwannoma, neurofibroma, atypical neurofibromatous neoplasms of uncertain biological potential, intraneural and soft tissue perineurioma, hybrid nerve sheath tumors, MPNST, and the recently renamed enigmatic tumor, malignant melanotic nerve sheath tumor, formerly referred to as melanotic schwannoma. We also discuss the diagnostic relevance of these neoplasms to specific genetic and familial syndromes of nerve, including neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis. In addition, we discuss updates in our understanding of the molecular alterations that represent key drivers of these neoplasms, including neurofibromatosis type 1 and type 2, SMARCB1, LZTR1, and PRKAR1A loss, as well as the acquisition of CDKN2A/B mutations and alterations in the polycomb repressor complex members (SUZ12 and EED) in the malignant progression to MPNST. In summary, this review covers practical aspects of pathologic diagnosis with updates relevant to neurosurgical practice.

Oligodeoxynucleotides containing unmethylated cytosine-guanine motifs are effective immunostimulants against pneumococcal meningitis in the immunocompetent and neutropenic host

BackgroundBacterial meningitis is a fatal disease with a mortality up to 30% and neurological sequelae in one fourth of survivors. Available vaccines do not fully protect against this lethal disease. Here, we report the protective effect of synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine motifs (CpG ODN) against the most frequent form of bacterial meningitis caused by Streptococcus pneumoniae.MethodsThree days prior to the induction of meningitis by intracerebral injection of S. pneumoniae D39, wild-type and Toll-like receptor (TLR9)−/− mice received an intraperitoneal injection of 100 μg CpG ODN or vehicle. To render mice neutropenic, anti-Ly-6G monoclonal antibody was daily administrated starting 4 days before infection with a total of 7 injections. Kaplan-Meier survival analyses and bacteriological studies, in which mice were sacrificed 24 h and 36 h after infection, were performed.ResultsPre-treatment with 100 μg CpG ODN prolonged survival of immunocompetent and neutropenic wild-type mice but not of TLR9−/− mice. There was a trend towards lower mortality in CpG ODN-treated immunocompetent and neutropenic wild-type mice. CpG ODN caused an increase of IL-12/IL-23p40 levels in the spleen and serum in uninfected animals. The effects of CpG ODN on bacterial concentrations and development of clinical symptoms were associated with an increased number of microglia in the CNS during the early phase of infection. Elevated concentrations of IL-12/IL-23p40 and MIP-1α correlated with lower bacterial concentrations in the blood and spleen during infection.ConclusionsPre-conditioning with CpG ODN strengthened the resistance of neutropenic and immunocompetent mice against S. pneumoniae meningitis in the presence of TLR9. Administration of CpG ODN decreased bacterial burden in the cerebellum and reduced the degree of bacteremia. Systemic administration of CpG ODN may help to prevent or slow the progression to sepsis of bacterial CNS infections in healthy and immunocompromised individuals even after direct inoculation of bacteria into the intracranial compartments, which can occur after sinusitis, mastoiditis, open head trauma, and surgery, including placement of an external ventricular drain.

Anatomical Features of the Deep Cervical Lymphatic System and Intrajugular Lymphatic Vessels in Humans.

Background: Studies in rodents have re-kindled interest in the study of lymphatics in the central nervous system. Animal studies have demonstrated that there is a connection between the subarachnoid space and deep cervical lymph nodes (DCLNs) through dural lymphatic vessels located in the skull base and the parasagittal area. Objective: To describe the connection of the DCLNs and lymphatic tributaries with the intracranial space through the jugular foramen, and to address the anatomical features and variations of the DCLNs and associated lymphatic channels in the neck. Methods: Twelve formalin-fixed human head and neck specimens were studied. Samples from the dura of the wall of the jugular foramen were obtained from two fresh human cadavers during rapid autopsy. The samples were immunostained with podoplanin and CD45 to highlight lymphatic channels and immune cells, respectively. Results: The mean number of nodes for DCLNs was 6.91 ± 0.58 on both sides. The mean node length was 10.1 ± 5.13 mm, the mean width was 7.03 ± 1.9 mm, and the mean thickness was 4 ± 1.04 mm. Immunohistochemical staining from rapid autopsy samples demonstrated that lymphatic vessels pass from the intracranial compartment into the neck through the meninges at the jugular foramen, through tributaries that can be called intrajugular lymphatic vessels. Conclusions: The anatomical features of the DCLNs and their connections with intracranial lymphatic structures through the jugular foramen represent an important possible route for the spread of cancers to and from the central nervous system; therefore, it is essential to have an in-depth understanding of the anatomy of these lymphatic structures and their variations.

Monro-Kellie Hypothesis: Increase of Ventricular CSF Volume after Surgical Closure of a Spinal Dural Leak in Patients with Spontaneous Intracranial Hypotension.

CSF loss in spontaneous intracranial hypotension disrupts a well-regulated equilibrium. We aimed to evaluate the volume shift between intracranial compartments in patients with spontaneous intracranial hypotension before and after surgical closure of the underlying spinal dural breach. In total, 19 patients with spontaneous intracranial hypotension with a proved spinal CSF leak investigated at our institution between July 2014 and March 2017 (mean age, 41.8 years; 13 women) were included. Brain MR imaging-based volumetry at baseline and after surgery was performed with FreeSurfer. In addition, the spontaneous intracranial hypotension score, ranging from 0 to 9, with 0 indicating very low and 9 very high probability of spinal CSF loss, was calculated. Total mean ventricular CSF volume significantly increased from baseline (15.3 mL) to posttreatment MR imaging (18.0 mL), resulting in a mean absolute and relative difference, +2.7 mL and +18.8% (95% CI, +1.2 to +3.9 mL; P < .001). The change was apparent in the early follow-up (mean, 4 days). No significant change in mean total brain volume was observed (1136.9 versus 1133.1 mL, P = .58). The mean spontaneous intracranial hypotension score decreased from 6.9 ± 1.5 at baseline to 2.9 ± 1.5 postoperatively. Our study demonstrated a substantial increase in ventricular CSF volume in the early follow-up after surgical closure of the underlying spinal dural breach and may provide a causal link between spinal CSF loss and spontaneous intracranial hypotension. The concomitant decrease in the spontaneous intracranial hypotension score postoperatively implies the restoration of an equilibrium within the CSF compartment.

Brain Radiation Induced Extracranial Abscopal Effects in Metastatic Melanoma

Historically, the brain has been viewed as a specialized neurovascular inert organ with a distinctive immune privilege. Therefore, radiation-induced extracranial abscopal effects would be considered an unusual phenomenon due to the difficulty of the immunogenic signaling molecules to travel across the blood-brain barrier (BBB). However, it is now possible that localized central nervous system radiation has the ability to disrupt the structural integrity of the BBB and increase its endothelial permeability allowing the free passage of immunogenic responses between the intracranial and extracranial compartments. Thus, the nascent tumor-associated antigens produced by localized brain radiation can travel across the BBB into the rest of the body to modulate the immune system and induce extracranial abscopal effects. In clinical practice, localized brain radiation therapy-induced extracranial abscopal effects are a rarely seen phenomenon in metastatic melanoma and other advanced cancers. In this article, we provide a detailed overview of the current state of knowledge and clinical experience of central nervous system radiation-induced extracranial abscopal effects in patients with malignant melanoma. Emerging data from a small number of case reports and cohort studies of various malignancies has significantly altered our earlier understanding of this process by revealing that the brain is neither isolated nor passive in its interactions with the body's immune system. In addition, these studies provide clinical evidence that the brain is capable of interacting actively with the extracranial peripheral immune system. Thus, localized radiation treatment to 1 or more locations of brain metastases can induce extracranial abscopal responses. Collectively, these findings clearly demonstrate that localized brain radiation therapy-induced abscopal effects traverses the BBB and trigger tumor regression in the nonirradiated extracranial locations.

Intracranial Volume After Cranial Vault Remodeling: To What Degree Does Intracranial Composition Change After Surgery?

BACKGROUND: The intracranial cavity is composed of brain tissue as well as cerebrospinal fluid (CSF), blood, and air. These fluid components allow volume to be shunted out of the intracranial region in the setting of skull-based compression to minimize the effect of compression on the brain. The degree of change to the intracranial compartment in the setting of craniosynostosis and the speed at which they occur and resolve after surgery are not fully understood. This study sought to rigorously analyze the intracranial volume compositions of patients with craniosynostosis prior to and after CVR. METHODS: The authors compared volume measurements for age-matched patients with unicoronal (n = 4), metopic (n = 4), and sagittal (n = 4) craniosynostosis. Intracranial segmentation and analysis were performed on Materialize Medical 21.0 (Materialise; Leuven, Belgium) using the following segmentation thresholds: bone 226-3066 HU, CSF -281-18 HU, and air 19-225 HU, and then manually edited utilizing typical segmentation techniques. On expert consultation, brain segmentation volumes were determined to be less reliable measurements than intracranial, CSF, and air volumes and were thus calculated by subtracting the other volumes from ICV. Paired t tests, one-way analysis of variance, and multiple regression analyses were performed on STATA 15.1 (StataCorp, College Station, TX). RESULTS: The average age at surgical repair was 8.7 ± 0.83 months. All postoperative imaging was performed between 3 and 5 days postoperatively aside from one patient with imaging at 19 days postoperatively. There was a significant increase in total ICV (913772.5 ± 102480.5 mm3 versus 1068165 ± 95752.5 mm3; P < 0.001) and intracranial air volume (18608.8 ± 9639.1 versus 53230.2 ± 32607.4; P = 0.001) after CVR. On subgroup analysis by affected suture, there was a significant increase in ICV (851748.9 ± 87438.1 versus 1043117 ± 149763; P = 0.009) and brain volume (737312.3 ± 80166.5 versus 829060.9 ± 61405.6; P = 0.021) in the metopic cohort and a significant increase in ICV (1006379 ± 31359.5 versus 1133497 ± 45574.1; P = 0.013) and intracranial air volume (18056.21± 5397.634 versus 53230.16± 32607; P = 0.001) in the sagittal cohort. The metopic cohort had the largest percent change in intracranial volume (18% ± 3.4%) and CSF volume (28% ± 24%). There were dramatic postoperative increases in intracranial air volumes in all cohorts (percent change: unicoronal 46% ± 16%; sagittal 58% ± 36%, metopic 58% ± 23%) at this postoperative time period. On multiple regression analysis with affected suture, type of CVR, age at repair and time from surgery to postoperative imaging as independent variables, age at repair was the only significant predictor of percent change in ICV (coef, −5.35; 95% CI, −10.2 to −0.51; P= 0.04) at the 0.05 significance level. CONCLUSION: The ICV increase created by CVR allows subsequent increases in brain, CSF, and air volumes in the early postoperative time period. Significant brain tissue volume increases were seen in the metopic cohort with significant intracranial air volume increases in the sagittal cohort. We hope to perform additional analysis with follow-up data to determine if some of the noted air volume increase is redistributed to brain tissue or CSF at a later time.

Antifungal drugs: An updated review of central nervous system pharmacokinetics.

Invasive fungal infections (IFIs) in the central nervous system (CNS) are particularly hard to treat and are associated with high morbidity and mortality rates. Four chemical classes of systemic antifungal agents are used for the treatment of IFIs (eg meningitis), including polyenes, triazoles, pyrimidine analogues and echinocandins. This review will address all of these classes and discuss their penetration and accumulation in the CNS. Treatment of fungal meningitis is based on the antifungal that shows good penetration and accumulation in the CNS. Pharmacokinetic data concerning the entry of antifungal agents into the intracranial compartments are faulty. This review will provide an overview of the ability of systemic antifungals to penetrate the CNS, based on previously published drug physicochemical properties and pharmacokinetic data, for evaluation of the most promising antifungal drugs for the treatment of fungal CNS infections. The studies selected and discussed in this review are from 1990 to 2019.

Imaging of Paranasal Sinus Infections in Children: A Review.

Paranasal sinuses (PNS) infections are common in children. They may cause common and well-known complications, but also, unusual and potentially devastating complications. Diagnosing PNS infections and complications in children requires knowledge of the unique anatomy of the nasal cavity and the PNS. In fetal life, nasal mucosa evaginations into the lateral nasal walls initiate the development of the PNS. The PNS continue to develop after birth and complete their maturation and pneumatization at different ages during childhood which makes the pattern of PNS infections determined by patient age. Complications are caused by direct spread of the infection to the orbit, face, intracranial or osseous structures or hematogenous spread of the infection to the intracranial structures. Emergent imaging studies are often necessary in the evaluation of the complications in pediatric patients when the symptoms persist for 10 days and/or if there is evidence of intracranial or orbital complications. In addition, immunocompromised children are especially vulnerable to developing unusual complications. Computed tomography (CT) is excellent for determining whether there is intraorbital extension of PNS disease. However, when the infection approaches the orbital apex, a magnetic resonance imaging (MRI) study with contrast is necessary to assess spread into the cavernous sinus and the intracranial compartment. The goal of this manuscript is to review and characterize imaging findings of PNS infections using CT and MRI allowing determination of the extent of PNS infections and their common and unusual complications in children. In addition, a summary of the development of the normal PNS is provided.

Intracranial tumors lead to sequestration of T cells in the bone marrow

Abstract Glioblastoma (GBM) is the most common primary, malignant brain tumor and is universally fatal. Immunotherapeutic intervention has shown some success in immunogenic solid tumors, but little efficacy in GBM. Tumor-imposed T cell deficits remain a major obstacle. Recently, we demonstrated that GBM patients exhibit local and systemic T cell dysfunction, severe lymphopenia and contracted lymphoid organs. These observations are recapitulated in multiple murine models of GBM. Although T cell numbers are decreased in blood, lymph nodes, and spleen, we find large numbers of T cells sequestered in the bone marrow of both patients and mice with GBM. T cell sequestration occurs not only in the setting of GBM, but with nearly any cancer placed intracranially. Intriguingly, none of the tumors tested, including GBM, induce sequestration of T cells in the bone marrow when implanted subcutaneously. These data suggest that the capacity to sequester T cells resides within the brain and is usurped by tumors of the intracranial compartment. Such capacities may well represent a novel mechanism of immune privilege. Sequestration of T cells follows loss of sphingosine-1 phosphate-receptor 1 (S1P1) from the T cell surface. Understanding the drivers of S1P1 loss will provide crucial insight for how brain tumors facilitate systemic immune alterations and permit the development of more effective immune-based strategies for brain tumor patients.

4-1BB Agonism Averts TIL Exhaustion and Licenses PD-1 Blockade in Glioblastoma and Other Intracranial Cancers

The success of checkpoint blockade against glioblastoma (GBM) has been disappointing. Anti-PD-1 strategies may be hampered by severe T-cell exhaustion. We sought to develop a strategy that might license new efficacy for checkpoint blockade in GBM. We characterized 4-1BB expression in tumor-infiltrating lymphocytes (TIL) from human GBM. We implanted murine tumor models including glioma (CT2A), melanoma (B16), breast (E0771), and lung carcinomas intracranially and subcutaneously, characterized 4-1BB expression, and tested checkpoint blockade strategies in vivo. Our data reveal that 4-1BB is frequently present on nonexhausted CD8+ TILs in human and murine GBM. In murine gliomas, 4-1BB agonism and PD-1 blockade demonstrate a synergistic survival benefit in a CD8+ T-cell-dependent manner. The combination decreases TIL exhaustion and improves TIL functionality. This strategy proves most successful against intracranial CT2A gliomas. Efficacy in all instances correlates with the levels of 4-1BB expression on CD8+ TILs, rather than with histology or with intracranial versus subcutaneous tumor location. Proffering 4-1BB expression to T cells licenses combination 4-1BB agonism and PD-1 blockade in models where TIL 4-1BB levels had previously been low and the treatment ineffective. Although poor T-cell activation and severe T-cell exhaustion appear to be limiting factors for checkpoint blockade in GBM, 4-1BB agonism obviates these limitations and produces long-term survival when combined with anti-PD-1 therapy. Furthermore, this combination therapy is limited by TIL 4-1BB expression, but not by the intracranial compartment, and therefore may be particularly well-suited to GBM.