Single-cell RNA sequencing reveals Immune Education promotes T cell survival in mice subjected to the cecal ligation and puncture sepsis model.

Background: Individual T cell responses vary significantly based on the microenvironment present at the time of immune response and on prior induced T cell memory. While the cecal ligation and puncture (CLP) model is the most commonly used murine sepsis model, the contribution of diverse T cell responses has not been explored. We defined T cell subset responses to CLP using single-cell RNA sequencing and examined the effects of prior induced T cell memory (Immune Education) on these responses. We hypothesized that Immune Education prior to CLP would alter T cell responses at the single cell level at a single, early post-CLP time point. Methods: Splenic T cells were isolated from C57BL/6 mice. Four cohorts were studied: Control, Immune-Educated, CLP, and Immune-Educated CLP. At age 8 weeks, Immune-Educated and Immune-Educated CLP mice received anti-CD3ϵ antibody; Control and CLP mice were administered an isotype control. CLP (two punctures with a 22-gauge needle) was performed at 12-13 weeks of life. Mice were sacrificed at baseline or 24-hours post-CLP. Unsupervised clustering of the transcriptome library identified six distinct T cell subsets: quiescent naïve CD4+, primed naïve CD4+, memory CD4+, naïve CD8+, activated CD8+, and CD8+ cytotoxic T cell subsets. T cell subset specific gene set enrichment analysis and Hurdle analysis for differentially expressed genes (DEGs) were performed. Results: T cell responses to CLP were not uniform - subsets of activated and suppressed T cells were identified. Immune Education augmented specific T cell subsets and led to genomic signatures favoring T cell survival in unoperated and CLP mice. Additionally, the combination of Immune Education and CLP effected the expression of genes related to T cell activity in ways that differed from CLP alone. Validating our finding that IL7R pathway markers were upregulated in Immune-Educated CLP mice, we found that Immune Education increased T cell surface IL7R expression in post-CLP mice. Conclusion: Immune Education enhanced the expression of genes associated with T cell survival in unoperated and CLP mice. Induction of memory T cell compartments via Immune Education combined with CLP may increase the model's concordance to human sepsis.

A multicenter retrospective study of heterogeneous tissue aggregates obstructing ventricular catheters explanted from patients with hydrocephalus.

BACKGROUND: Implantation of ventricular catheters (VCs) to drain cerebrospinal fluid (CSF) is a standard approach to treat hydrocephalus. VCs fail frequently due to tissue obstructing the lumen via the drainage holes. Mechanisms driving obstruction are poorly understood. This study aimed to characterize the histological features of VC obstructions and identify links to clinical factors. METHODS: 343 VCs with relevant clinical data were collected from five centers. Each hole on the VCs was classified by degree of tissue obstruction after macroscopic analysis. A subgroup of 54 samples was analyzed using immunofluorescent labelling, histology and immunohistochemistry. RESULTS: 61.5% of the 343 VCs analyzed had tissue aggregates occluding at least one hole (n = 211) however the vast majority of the holes (70%) showed no tissue aggregates. Mean age at which patients with occluded VCs had their first surgeries (3.25 yrs) was lower than in patients with non-occluded VCs (5.29 yrs, p < 0.02). Mean length of time of implantation of occluded VCs, 33.22 months was greater than for non-occluded VCs, 23.8 months (p = 0.02). Patients with myelomeningocele had a greater probability of having an occluded VC (p = 0.0426). VCs with occlusions had greater numbers of macrophages and astrocytes in comparison to non-occluded VCs (p < 0.01). Microglia comprised only 2-6% of the VC-obstructing tissue aggregates. Histologic analysis showed choroid plexus occlusion in 24%, vascularized glial tissue occlusion in 24%, prevalent lymphocytic inflammation in 29%, and foreign body giant cell reactions in 5% and no ependyma. CONCLUSION: Our data show that age of the first surgery and length of time a VC is implanted are factors that influence the degree of VC obstruction. The tissue aggregates obstructing VCs are composed predominantly of astrocytes and macrophages; microglia have a relatively small presence.

The role of lumboperitoneal shunts in managing chronic hydrocephalus with slit ventricles.

OBJECTIVELumboperitoneal (LP) shunts have a role not only in pseudotumor cerebri, but also in patients with slit-like ventricles who are treated with CSF shunting on a chronic basis. Hesitation to utilize LP shunts is based on previous conventional beliefs including the tendency for overdrainage, difficulties accessing the shunt to tap or revise, and risk of progressive cerebellar tonsillar herniation. The authors hypothesized that the use of horizontal-vertical (HV) valves may reduce the risk of these complications, particularly overdrainage and development of Chiari malformation.METHODSAll pediatric cases involving patients treated with an LP shunt at the Children's Hospital of Michigan were reviewed in this retrospective case series. A total of 143 patients with hydrocephalus were treated with LP shunts from 1997-2015 (follow-up range 8 months-8 years, median 4.2 years). Patients with pseudotumor cerebri underwent placement of an LP shunt as a primary procedure. In patients with slit ventricles from chronically treated hydrocephalus or repeated shunt malfunctions from proximal catheter obstruction, a lumbar drain was inserted to assess candidacy for conversion to an LP shunt. In patients who tolerated the lumbar drain and demonstrated communication of the ventricles with the spinal cisterns, treatment was converted to an LP shunt. All patients included in the series had undergone initial shunt placement between birth and age 16 years.RESULTSIn 30% of patients (n = 43), LP shunts were placed as the initial shunt treatment; in 70% (n = 100), treatment was converted to LP shunts from ventriculoperitoneal (VP) shunts. The patients' age at insertion of or conversion to an LP shunt ranged from 1 to 43 years (median 8.5 years). Of the patients with clear pre-LP and post-LP shunt follow-up imaging, none were found to develop an acquired Chiari malformation. In patients with pre-existing tonsillar ectopia, no progression was noted on follow-up MRIs of the brain in these patients after LP shunt insertion. In our LP shunt case series, no patient presented with acute deterioration from shunt malfunction.CONCLUSIONSConversion to an LP shunt may minimize acute deterioration from shunt malfunction and decrease morbidity of repeated procedures in patients with chronically shunt-treated hydrocephalus and small ventricles. In comparison to previously published case series of LP shunt treatment, the use of LP shunts in conjunction with HV valves may decrease the overall risk of cerebellar tonsillar herniation. The use of an LP shunt may be an alternative in the management of slit ventricles when VP shunting repeatedly fails.

Apparent diffusion coefficient mapping in medulloblastoma predicts non-infiltrative surgical planes.

INTRODUCTION: An appropriate surgical approach for posterior fossa lesions is to start tumor removal from areas with a defined plane to where tumor is infiltrating the brainstem or peduncles. This surgical approach minimizes risk of damage to eloquent areas. Although magnetic resonance imaging (MRI) is the current standard preoperative imaging obtained for diagnosis and surgical planning of pediatric posterior fossa tumors, it offers limited information on the infiltrative planes between tumor and normal structures in patients with medulloblastomas. Because medulloblastomas demonstrate diffusion restriction on apparent diffusion coefficient map (ADC map) sequences, we investigated the role of ADC map in predicting infiltrative and non-infiltrative planes along the brain stem and/or cerebellar peduncles by medulloblastomas prior to surgery. METHODS: Thirty-four pediatric patients with pathologically confirmed medulloblastomas underwent surgical resection at our facility from 2004 to 2012. An experienced pediatric neuroradiologist reviewed the brain MRIs/ADC map, assessing the planes between the tumor and cerebellar peduncles/brain stem. An independent evaluator documented surgical findings from operative reports for comparison to the radiographic findings. The radiographic findings were statistically compared to the documented intraoperative findings to determine predictive value of the test in identifying tumor infiltration of the brain stem cerebellar peduncles. RESULTS: Twenty-six patients had preoperative ADC mapping completed and thereby, met inclusion criteria. Mean age at time of surgery was 8.3 ± 4.6 years. Positive predictive value of ADC maps to predict tumor invasion of the brain stem and cerebellar peduncles ranged from 69 to 88 %; negative predictive values ranged from 70 to 89 %. Sensitivity approached 93 % while specificity approached 78 %. CONCLUSIONS: ADC maps are valuable in predicting the infiltrative and non-infiltrative planes along the tumor and brain stem interface in medulloblastomas. Inclusion and evaluation of ADC maps in preoperative evaluation can assist in surgical resection planning in patients with medulloblastoma.

Effect of molding helmets on intracranial pressure and head shape in nonsurgically treated sagittal craniosynostosis patients.

OBJECTIVE Cranial vault expansion is performed in pediatric patients with craniosynostosis to improve head shape. Another argument for performing total cranial vault reconstruction is the potential reduction in the harmful effects of elevated intracranial pressure (ICP) that are associated with craniosynostosis. Alternatively, molding helmets have been shown to improve the cranial index (CI) in patients with sagittal synostosis without surgery. However, it is unknown if the use of molding helmets without surgery contributes to adverse changes in ICP. The effect of molding helmets on ICP and CI in patients with sagittal synostosis was investigated. METHODS A prospective cohort study of 24 pediatric patients with sagittal synostosis who planned to undergo total cranial reconstruction was performed from 2011 to 2014 at the Children's Hospital of Michigan. A preoperative molding helmet was used in 13 patients, and no molding helmet was used in 11 patients. End-tidal carbon dioxide, patient positioning, level of sedation, type of anesthetic, and the monitoring site at the time of intraoperative recording were regulated and standardized to establish the accuracy of the ICP readings. CI and head circumference were monitored for each patient. RESULTS The mean duration of the preoperative use of the molding helmet was 17 weeks (range 7-37 weeks). Under controlled settings, the average intraoperative ICP was 7.2 mm Hg (range 2-18 mm Hg) for patients treated with a preoperative molding helmet and 9.5 mm Hg (range 2-22 mm Hg) for patients with no preoperative molding helmet. ICP was not significantly different between the 2 groups, suggesting that the use of a molding helmet in this population is safe. The average CI at the time of helmet placement was 0.70 (range 0.67-0.73), and this improved to an average of 0.74 (range 0.69-0.79) after using the molding helmet for a mean of 17 weeks. CONCLUSIONS ICPs were not significantly different with the use of a preoperative molding helmet, refuting the prevailing thought that molding helmets would be detrimental in children who have craniosynostosis. The use of molding helmet in this population of patients improves head shape and does not adversely affect ICP.

Endoscopic corpus callosotomy and hemispherotomy.

OBJECT: Corpus callosotomy and hemispherotomy are conventionally performed via a large craniotomy with the aid of a microscope for children with intractable epilepsy. Primary technical considerations include completeness of disconnection and blood loss. The authors describe an endoscopic technique performed through a microcraniotomy for these procedures. METHODS: Four patients with drop attacks and 2 with intractable seizures related to a neonatal stroke underwent endoscopic complete corpus callosotomy and hemispherotomy, respectively. The surgeries were performed through a 2- to 3-cm precoronal microcraniotomy. Interhemispheric dissection to the corpus callosum was done using the standard technique. Subsequently, the bimanual technique with a suction device mounted on an endoscope was used to perform a complete corpus callosotomy, including interforniceal and anterior commissure disconnection. In patients who had hemispherotomy, the fornix was resected posteriorly and lateral disconnection was done by unroofing the temporal horn. Anteriorly, endoscopic corticectomy was done along the ipsilateral anterior cerebral artery to reach the bifurcation of the internal carotid artery to complete the anterior disconnection. Postoperative MRI and diffusion tensor imaging (DTI) of the brain were performed to confirm complete disconnection. RESULTS: The procedure was accomplished successfully in all patients, with excellent visualization secured. None of the patients required a blood transfusion. Postoperative MRI and DTI confirmed completeness of the disconnection. Patients who underwent corpus callosotomy had complete resolution of drop attacks at a mean follow-up of 6 months, and patients who underwent hemispherotomy became seizure free. CONCLUSIONS: Endoscopic corpus callosotomy and hemispherotomy are surgically feasible procedures associated with minimal blood loss, minimal risk, and excellent visualization.

Interhemispheric endoscopic resection of large intraventricular and thalamic tumors.

A transfrontal route is the traditional endoscopic approach to intraventricular tumors. Small lesions can be biopsied using the parallel port channel of the endoscope. For larger tumors a ventriculoport can be used for resection. This technique nevertheless requires traversing the brain tissue, is difficult in the setting of small ventricles, and allows only limited mobility. The authors describe the endoscopic resection of large intraventricular tumors via an interhemispheric route using rigid suction with a mounted endoscope, and thus circumventing some of the problems with the traditional approach.

Effect of molding helmet on head shape in nonsurgically treated sagittal craniosynostosis.

OBJECT: Sagittal craniosynostosis is traditionally considered to be a surgical condition. Poor results of simple suturectomy follow from early reclosure of the suture. A wider craniectomy or use of interposing materials has not improved the outcome. However, endoscopic suturectomy supplemented with postoperative use of a molding helmet has shown good results. Because suturectomy reunites within 8-12 weeks of surgery, the authors questioned if the improved outcome was primarily related to use of the helmet. METHODS: In 4 patients whose families opted for calvarial reconstruction when the infant was 4-6 months old, instead of endoscopic suturectomy, a molding helmet was used to minimize compensatory changes in the interim. Patients underwent 3D CT scanning to confirm craniosynostosis. Follow-up visits were made at intervals of 4 weeks for adjustment of the helmet, head circumference measurements, clinical photographs, and cranial index measurement. RESULTS: There was significant improvement in the head shape within 6 weeks of use of the molding helmet. The cranial index score improved from a mean (± SD) of 67% ± 3% to 75% ± 2%. CONCLUSIONS: These cases demonstrate that molding helmets improve head shape even without a suturectomy in patients with sagittal craniosynostosis, challenging the traditional view.

Pure endoscopic removal of pineal region tumors.

PURPOSE: Endoscopic resection of pineal tumors using an endoscope with a mounted rigid suction that allows bimanual handling of the tumor for resection. This contrasts to the established method of biopsy of pineal tumors through intraventricular approach. METHODS: Two patients, one with a cystic lesion in the pineal region and one with a large pineal tumor, were operated in sitting position through a subtorcular approach. Endoscope was held in the left hand with suction tip extending beyond the tip through its instrument channel. Regular microsurgical instrumentation/CUSA/Nico Aspirator was used with the right hand for dissection, cutting, and removing the tumor under endoscopic vision. RESULT: Surgeon comfort was superior to when microscope is used in sitting position. Complete resection was achieved in all cases. CONCLUSION: The two-handed endoscopic technique using a mounted suction on the endoscope as described is a safe and effective strategy for resecting pineal region tumors.

Pediatric spinal clear cell meningioma. Case report.

In this report the authors describe a unique case of spinal clear cell meningioma in a 13-year-old girl. Clear cell meningiomas (CCMs) are not uncommon. To the authors' knowledge, 14 cases of pediatric CCM occurring in the spinal canal have been reported. Factors lending resistance to meningioma initiation and invasion are analyzed. This 13-year-old girl presented with pain radiating down her left leg. Admission MR imaging showed an inhomogeneous enhancing intradural-extramedullary mass at the L4-5 level. Resection revealed a CCM, and radiotherapy was subsequently administered. Postoperatively there has been no recurrence in > 2 years. In this paper the authors report a case of CCM and provide a comprehensive literature review on this disease. Current recommendations for its management are still debatable, especially in the pediatric population, and the authors propose an algorithm for its treatment and surveillance.

Thrombosis associated with ventriculoatrial shunts.

OBJECT: In this single-center study, the authors examined the clinical characteristics, risk factors, treatment strategies, and outcomes in patients with thrombosis associated with ventriculoatrial (VA) shunts. METHODS: Inpatient and outpatient charts of patients who underwent treatment and follow-up in the Hematology-Oncology Division at the authors' institution and in whom thrombosis developed secondary to a VA shunt placement were reviewed. A complete thrombophilia work-up was performed in each patient, and these records were also reviewed. Treatment including medical and surgical management was noted and outcome data were recorded. RESULTS: Resolution of thrombosis was seen after anticoagulation therapy in all patients; this may be an alternative to surgical therapy. CONCLUSIONS: Patients with VA shunts represent a unique group at risk for thrombosis. The duration of anticoagulation therapy must be individualized. However, larger studies are needed to evaluate the efficacy of screening for asymptomatic thrombosis and to investigate the role of prophylactic anticoagulation.

Value of overnight monitoring of intracranial pressure in hydrocephalic children.

OBJECTIVE: Exaggerated nocturnal intracranial pressure (ICP) dynamics are commonly observed in hydrocephalic children with a compromise of CSF compensatory reserve capacity. Successful shunting restores this cerebrospinal reserve. We used ICP overnight monitoring combined with positional maneuvers in complex hydrocephalic children with a suspected shunt malfunction for the assessment of shunt function. METHODS: In 32 hydrocephalic children, we performed 65 computerized overnight recordings and 25 positional maneuvers. Baseline ICP was considered abnormal if it exceeded the operating pressure of the shunt by more than 2.5 mm Hg. The maximum ICP (normal = <25 mm Hg), RAP coefficient (the correlation coefficient between pulse amplitude and mean intracranial pressure, which indicates pressure volume compensatory reserve; normal = <0.6), magnitude of slow waves (SLOW) and ICP pulse amplitude (AMP) were calculated for each night. RESULTS: Using baseline ICP, maximum ICP and RAP, 19 recordings were classified as 'normal' (group 1), 13 as 'questionable' (group 2), and 33 as 'pathological' (group 3) indicating shunt dysfunction or active hydrocephalus. ICP, AMP, RAP and SLOW were significantly different between groups and significantly elevated in group 3 compared to group 1. Positional tests identified shunt overdrainage in 5 of 25 occasions. In patients of group 1, who underwent revision, shunts turned out to be functional. All patients of group 3 eventually underwent shunt revision with improvement of symptoms thereafter. CONCLUSION: Computerized ICP monitoring can benefit the assessment of shunt function, and can accurately characterize the status of CSF compensation in shunted children with a complex presentation.

Management of lumbar shunt site swelling in children.

OBJECT: The aim of this study was to define the origin and management of lumbar shunt site swelling/cerebrospinal fluid (CSF) leak seen in children who underwent placement of a percutaneous lumbar shunt due to recurrent problems with a ventricular shunt. METHODS: Fifty-seven children with a lumbar shunt were analyzed. Episodes of swelling along the lumbar shunt site, presenting symptoms, origin of the CSF leak, and surgical outcome were recorded. RESULTS: Twenty patients had 30 episodes of CSF leak/swelling at a mean interval of 92 +/- 233 days (+/- standard deviation) after placement or revision. There were 7 episodes of an external CSF leak; 5 of marked swelling; and 18 episodes of headache, dizziness, and swelling. In 4 patients, the cause of CSF leakage was a fracture/disconnection or dislocation of the proximal catheter. In the remaining patients, CSF leakage was from around the proximal catheter entry point into the spinal dura (with a rate of 16.9% for placement and 15.7% for revision/reinsertion). Interlaminar removal of the existing catheter, microsurgical repair of the leak, and replacement through an opening made with the stylet of a 14-gauge Tuohy needle (Medtronic Neurosurgery) was most effective compared with percutaneous blood patch, pericatheter fascial suture, and percutaneous repositioning of the proximal catheter or downgrading valve pressure. CONCLUSIONS: Lumbar shunt site swelling is predominantly a consequence of pericatheter CSF leakage from the mismatch in the dural opening, which corresponds to the outer diameter of the 14-gauge Tuohy needle and the smaller proximal lumbar catheter. It is best managed by direct repair of the defect through a microsurgical interlaminar approach and recannulation of the dura by using only the stylet of a 14-gauge Tuohy needle.

Delayed lateral rectus palsy following resection of a pineal cyst in sitting position: direct or indirect compressive phenomenon?

A rare case of delayed lateral rectus palsy in a patient following resection of a pineal lesion in the sitting position is presented. Postoperative pneumocephalus is common following craniospinal surgical intervention in the sitting position. The sixth cranial nerve is frequently injured because of its prolonged intracranial course. A 13-year-old girl was evaluated for unremitting headaches. No focal deficits were demonstrated on neurological examination. Magnetic resonance imaging revealed a cystlike pineal region mass with peripheral enhancement following intravenous contrast administration. A supracerebellar infratentorial craniotomy was performed in the sitting position, and complete resection of the lesion was achieved. Her postoperative course was complicated by sixth nerve palsy on the third postoperative day. Her symptoms improved with conservative management. The occurrence of sixth cranial nerve palsy secondary to pneumocephalus is a rare entity. Even rarer is the report of this anomaly following craniotomy in the sitting position. This patient's symptoms manifested in a delayed fashion. Although uncommon, this complication should be considered in patients undergoing cranial or spinal surgical interventions in this position.

The role of lumbar shunts in the management of slit ventricles: does the slit-ventricle syndrome exist?

OBJECT: Slit-ventricle syndrome (SVS) is a confusing description of presentations in patients with chronic shunt-treated hydrocephalus. These patients are prone to acute deterioration with recurrent malfunction. The authors describe the clinical profile and management outcome of using lumboperitoneal (LP) shunts in this population of patients. METHODS: Thirty-three patients with slit ventricles and recurrent malfunctions were converted to LP shunts (mean age 12 years). The initial ventricular shunt was placed at a mean age of 16.5 months. Ten patients had failed endoscopic third ventriculostomies prior to placement of their LP shunt. At a previous presentation, in 11 patients suspected to have SVS following revision of the shunt, intracranial pressure normalized after insertion of a contralateral shunt, suggesting that their ventricles were isolated. The rate of infection and malfunction was compared before and after conversion to an LP shunt. Twenty-seven patients were successfully converted to LP shunts. Four of the 11 patients with isolated ventricles required ventricular shunts in addition to the LP shunt. During a mean follow-up period of 16.7 months, the malfunction rate per patient decreased from 4.81 for ventriculoperitoneal shunts, prior to conversion to 1.48 after conversion to LP shunts, a statistically significant reduction (p < 0.000). No significant difference was found in the rate of shunt infections (7.1% for VP shunts and 9.6% for LP shunts, p = 0.44). No patient presented with acute symptoms following malfunction of an LP shunt or suffered from a Chiari I malformation. CONCLUSIONS: Conversion to an LP shunt is a safe and effective procedure in patients prone to rapid decompensation and recurrent shunt malfunctions from small, slitlike ventricles. The term SVS is confusing. The condition is a manifestation of an unrecognized slitlike isolated ventricle and should be abandoned.

Endoscopic fenestration and coagulation shrinkage of suprasellar arachnoid cysts. Technical note.

The authors describe their experience with endoscopic fenestration of suprasellar cysts followed by shrinkage coagulation of the cysts to restore the anatomy in eight patients. Seven children ranging in age from 8 months to 4.5 years and one adult 24 years of age were treated. Four of the children presented with megacephaly and the other patients with malfunction of a shunt that had been placed previously for hydrocephalus. Endoscopic fenestration of the cyst dome was performed followed by shrinkage of the lesion by means of endoscopic coagulation. Follow-up studies included immediate and late postoperative magnetic resonance imaging, assessment of growth velocity and the body mass index (BMI), and an endocrine profile if indicated by a failure of growth or precocious puberty. Good intraoperative cyst shrinkage was achieved in all seven children. This was maintained on imaging studies at a mean follow-up period of 35 months. There was no significant procedure-associated morbidity. Hydrocephalus resolved in four patients who did not have a preexisting shunt. One of the four patients who had a shunt preoperatively became shunt free. The rest of the patients with preexisting shunts remained shunt dependent despite good resolution of the cyst. During a mean follow-up period of 52 months, the height, growth velocity, and BMI of each patient remained within two standard deviations of normal. In one patient there was a suspicion of precocious puberty, but the endocrine profile was normal; in another patient precocious puberty developed and required treatment. The presented technique is safe and prevents cyst recurrence and obstruction of the aqueduct by remnants of the cyst wall-the two main reasons for failure of a simple endoscopic fenestration.