Pro-inflammatory cerebrospinal fluid profile of neonates with intraventricular hemorrhage: clinical relevance and contrast with CNS infection.

BACKGROUND: Interpretation of cerebrospinal fluid (CSF) studies can be challenging in preterm infants. We hypothesized that intraventricular hemorrhage (IVH), post-hemorrhagic hydrocephalus (PHH), and infection (meningitis) promote pro-inflammatory CSF conditions reflected in CSF parameters. METHODS: Biochemical and cytological profiles of lumbar CSF and peripheral blood samples were analyzed for 81 control, 29 IVH grade 1/2 (IVH1/2), 13 IVH grade 3/4 (IVH3/4), 15 PHH, 20 culture-confirmed bacterial meningitis (BM), and 27 viral meningitis (VM) infants at 36.5 ± 4 weeks estimated gestational age. RESULTS: PHH infants had higher (p < 0.02) CSF total cell and red blood cell (RBC) counts compared to control, IVH1/2, BM, and VM infants. No differences in white blood cell (WBC) count were found between IVH3/4, PHH, BM, and VM infants. CSF neutrophil counts increased (p ≤ 0.03) for all groups compared to controls except IVH1/2. CSF protein levels were higher (p ≤ 0.02) and CSF glucose levels were lower (p ≤ 0.003) for PHH infants compared to all other groups. In peripheral blood, PHH infants had higher (p ≤ 0.001) WBC counts and lower (p ≤ 0.03) hemoglobin and hematocrit than all groups except for IVH3/4. CONCLUSIONS: Similarities in CSF parameters may reflect common pathological processes in the inflammatory response and show the complexity associated with interpreting CSF profiles, especially in PHH and meningitis/ventriculitis.

Complications associated with combined direct and indirect bypass in Moyamoya Disease: A meta-analysis.

Bypass revascularization helps prevent complications in Moyamoya Disease (MMD). To systematically review complications associated with combined direct and indirect (CB) bypass in MMD and analyze differences between the adult and pediatric populations. A systematic literature review was conducted per PRISMA guidelines. PUBMED, Cochrane Library, Web of Science, and CINAHL, were queried from January 1980 to March 2022. Complications were defined as any event in the immediate post-surgical period of a minimum 3 months follow-up. Exclusion criteria included lack of surgical complication reports, non-English articles, and CB unspecified or reported separately. 18 final studies were included of 1580 procured. 1151 patients (per study range = 10-150, mean = 63.9) were analyzed. 9 (50.0%) studies included pediatric patients. There were 32 total hemorrhagic, 74 total ischemic and 16 total seizure complications, resulting in a rate of 0.04 (95% CI 0.03, 0.06), 0.7 (95% CI 0.04, 0.10) and 0.03 (95% CI 0.02, 0.05), respectively. The rate of hemorrhagic complications in the pediatric showed no significant difference from the adult subgroup (0.03 (95% CI 0.01-0.08) vs. 0.06 (95% CI 0.04-0.10, p = 0.19), such as the rate of ischemic complications (0.12 (95% CI 0.07-0.23) vs. 0.09 (95% CI 0.05-0.14, p = 0.40). Ischemia is the most common complication in CB for MMD. Pediatric patients had similar hemorrhagic and ischemic complication rates compared to adults.

Neurosurgical management of cervicomedullary compression, spinal stenosis, and hydrocephalus in pediatric achondroplasia: a systematic review.

OBJECTIVE: Pediatric achondroplasia is often associated with conditions requiring neurosurgical intervention, including CSF diversion and multilevel spinal decompression. However, there is a lack of clinical guidelines and reliable estimates of the benefits and risks of these interventions. This study aimed to summarize the literature on the neurosurgical management of pediatric achondroplasia patients in order to aid in determining optimal treatment and standardization of care. METHODS: A systematic review of peer-reviewed studies with an objective diagnosis of achondroplasia, patient demographic information, and available data on neurosurgical interventions performed before 18 years of age for cervicomedullary compression, spinal stenosis, and hydrocephalus was performed. Study quality and risks of bias were assessed using standardized scores. Independent patient data on surgical indications, outcomes, reoperations, and complication risks were aggregated using means and percentages. RESULTS: Of 204 records, 25 studies with 287 pediatric achondroplasia patients (mean age 25 ± 36 months) treated for cervicomedullary compression (n = 153), spinal stenosis (n = 100), and obstructive hydrocephalus (n = 34) were evaluated. Symptomatic cervicomedullary compression occurred early in life (mean age 31 ± 25 months), with apnea (48%), T2-weighted MRI cord signal (28%), myelopathy (27%), and delayed motor skills (15%) requiring foramen magnum decompression observed in 99% of patients, as well as cervical laminectomy in 65% of patients. Although 91% of treated patients had resolution of symptoms, 2% mortality, 9% reoperation, and 21% complication rates were reported. Spinal stenosis was treated in relatively older children (mean age 13 ± 3 years) with laminectomy (23%), as well as with instrumented fusion (73%) for neurogenic claudication (59%), back pain (15%), and sciatica (8%). Although 95% of patients had symptom resolution after surgery, 17% reported complications and 18% required reoperation. Of the hydrocephalus patients (mean age 56 ± 103 months), half were treated with endoscopic third ventriculostomy (ETV) and half had a shunt placed for progressive ventriculomegaly (66%), headaches (32%), and delayed cognitive development (4%). The shunted patients had a 3% mortality rate and an average of 1.5 shunt revisions per patient. None of the patients who underwent ETV as the primary procedure required a revision. CONCLUSIONS: Neurosurgical intervention for pediatric achondroplasia conditions, including cervicomedullary compression, spinal stenosis, and hydrocephalus, is associated with high recovery rates and good outcomes. However, complications and reoperations are common. Further studies with follow-up into adulthood are needed to evaluate the long-term outcomes.

Treatment of hydrocephalus following posterior fossa tumor resection: a multicenter collaboration from the Hydrocephalus Clinical Research Network.

OBJECTIVE: Persistent hydrocephalus following posterior fossa brain tumor (PFBT) resection is a common cause of morbidity in pediatric brain tumor patients, for which the optimal treatment is debated. The purpose of this study was to compare treatment outcomes between VPS and ETV in patients with persistent hydrocephalus following surgical resection of a PFBT. METHODS: A post-hoc analysis was performed of the Hydrocephalus Clinical Research Network (HCRN) prospective observational study evaluating VPS and ETV for pediatric patients. Children who experienced hydrocephalus secondary to PFBT from 2008 to 2021 were included. Primary outcomes were VPS/ETV treatment failure and time-to-failure (TTF). RESULTS: Among 241 patients, the VPS (183) and ETV (58) groups were similar in age, extent of tumor resection, and preoperative ETV Success Score. There was no difference in overall treatment failure between VPS and ETV (33.9% vs 31.0%, p = 0.751). However, mean TTF was shorter for ETV than VPS (0.45 years vs 1.30 years, p = 0.001). While major complication profiles were similar, compared to VPS, ETV patients had relatively higher incidence of minor CSF leak (10.3% vs. 1.1%, p = 0.003) and pseudomeningocele (12.1% vs 3.3%, p = 0.02). No ETV failures were identified beyond 3 years, while shunt failures occurred beyond 5 years. Shunt infections occurred in 5.5% of the VPS cohort. CONCLUSIONS: ETV and VPS offer similar overall success rates for PFBT-related postoperative hydrocephalus. ETV failure occurs earlier, while susceptibility to VPS failure persists beyond 5 years. Tumor histology and grade may be considered when selecting the optimal means of CSF diversion.

Use of cortical volume to predict response to temporary CSF drainage in patients with idiopathic normal pressure hydrocephalus.

OBJECTIVE: Temporary drainage of CSF with lumbar puncture or lumbar drainage has a high predictive value for identifying patients with suspected idiopathic normal pressure hydrocephalus (iNPH) who may benefit from ventriculoperitoneal shunt insertion. However, it is unclear what differentiates responders from nonresponders. The authors hypothesized that nonresponders to temporary CSF drainage would have patterns of reduced regional gray matter volume (GMV) as compared with those of responders. The objective of the current investigation was to compare regional GMV between temporary CSF drainage responders and nonresponders. Machine learning using extracted GMV was then used to predict outcomes. METHODS: This retrospective cohort study included 132 patients with iNPH who underwent temporary CSF drainage and structural MRI. Demographic and clinical variables were examined between groups. Voxel-based morphometry was used to calculate GMV across the brain. Group differences in regional GMV were assessed and correlated with change in results on the Montreal Cognitive Assessment (MoCA) and gait velocity. A support vector machine (SVM) model that used extracted GMV values and was validated with leave-one-out cross-validation was used to predict clinical outcome. RESULTS: There were 87 responders and 45 nonresponders. There were no group differences in terms of age, sex, baseline MoCA score, Evans index, presence of disproportionately enlarged subarachnoid space hydrocephalus, baseline total CSF volume, or baseline white matter T2-weighted hyperintensity volume (p > 0.05). Nonresponders demonstrated decreased GMV in the right supplementary motor area (SMA) and right posterior parietal cortex as compared with responders (p < 0.001, p < 0.05 with false discovery rate cluster correction). GMV in the posterior parietal cortex was associated with change in MoCA (r2 = 0.075, p < 0.05) and gait velocity (r2 = 0.076, p < 0.05). Response status was classified by the SVM with 75.8% accuracy. CONCLUSIONS: Decreased GMV in the SMA and posterior parietal cortex may help identify patients with iNPH who are unlikely to benefit from temporary CSF drainage. These patients may have limited capacity for recovery due to atrophy in these regions that are known to be important for motor and cognitive integration. This study represents an important step toward improving patient selection and predicting clinical outcomes in the treatment of iNPH.

Characteristics of shunt failure in 38,095 adult shunt insertion surgeries: a systematic review and meta-analysis.

OBJECTIVE: The management of excess CSF in patients with hydrocephalus typically requires using a shunt to divert CSF. Unfortunately, there is a high rate of shunt failure despite improvements in device components and insertion techniques. Reoperation is frequently necessary, which contributes to patient harm and increased healthcare costs. While factors affecting shunt failure are well defined in the pediatric population, information regarding adults is lacking. The authors undertook a systematic review and meta-analysis to determine how shunt failure in the adult population is reported and investigated the etiologies of shunt failure. METHODS: This review is reported according to PRIMSA and utilized the MEDLINE, Embase, and Google Scholar databases. Abstracts were screened by two independent reviewers, and data were extracted in duplicate by two independent reviewers. Statistical analyses were performed using SPSS and Stata. RESULTS: The pooled rates of shunt failure were 10% (95% CI 5%-15%) in studies with a mean follow-up time of less than 1 year, 12% (95% CI 8%-14%) with a follow-up time between 1 and 2 years, and 32% in studies with a follow-up time of 2 years or greater (95% CI 19%-43%). The pooled rate of failure was 17% across all studies. The most common cause of shunt failure was obstruction at 3.0% (95% CI 2%-4%), accounting for 23.2% of shunt failures. Infection was the second most common at 2.8% (95% CI 2%-3%), accounting for 22.5% of shunt failures. The most common location of shunt failure was the distal catheter, with a failure rate of 4.0% (95% CI 3%-5%), accounting for 33.4% of shunt failures. The definition of shunt failure was heterogeneous and varied depending on institutional practices. The combination of symptoms with either CT or MRI was the most frequently reported method for assessing shunt failure. CONCLUSIONS: Important variation regarding how to define, investigate, and report shunt failure was identified. The overall shunt failure rate in adults is at least 32% after 2 years, which, while lower than that typically reported in the pediatric population, is significant. The most common causes of shunt failure in adults are infection and obstruction. The most common site of failure occurred at the distal catheter, highlighting the need to develop strategies to both report and mitigate distal shunt failure in adult shunt patients.

Surgical treatment of craniovertebral junction instability in children with Down syndrome: a systematic review.

OBJECTIVE: Down syndrome (DS) affects 1 in 700 live births and approximately one-third of patients develop craniovertebral junction (CVJ) instability, diagnosed by clinical examination and radiological measures such as the atlantodens interval (ADI) and space available for the cord (SAC). Patients with symptomatic CVJ instability are at increased risk for spinal cord injury. There are no guidelines for surgical management of CVJ instability in DS, the existing literature is sparse, and there is a lack of consistent pediatric data. This systematic review aimed to synthesize practice patterns of the surgical management of CVJ stability in pediatric DS patients to facilitate future standardization of care. METHODS: Peer-reviewed studies reporting surgical management of CVJ instability in pediatric DS patients were systematically reviewed. Inclusion criteria were studies reporting primary data on patients younger than 18 years with DS, who had CVJ instability evaluation and underwent surgical treatment. Bias risk was assessed. Descriptive statistics of the independent patient data were presented. Interval variables were analyzed using the Wilcoxon rank-sum test. RESULTS: Of 1056 records, 38 studies were included. Of the included patients, 169 (6%) underwent surgery. The surgical indication was symptomatic, radiologically confirmed CVJ instability in 81% of the patients, presenting with myelopathy (30%), weakness (25%), abnormal gait (24%), torticollis (15%), and neck pain (14%). A cutoff of ADI ≥ 4 mm or SAC ≤ 14 mm, cord compression, cord signal change, and anomalous bony anatomy were used in diagnosing CVJ instability. Surgical approaches focused on internal fixation with posterior occipitocervical or atlantoaxial instrumented fusion in 57% and 44% of patients, respectively. Autograft, wiring, and allograft constructs were used in 48%, 45%, and 9% of patients. Anterior cervical approaches were performed in 6% of patients. Preoperative and postoperative external orthoses were used in approximately 50% of patients. The surgical mortality rate was 3%, and the complication rate was 36%. CONCLUSIONS: Assessment of CVJ instability in DS is based on radiographic and clinical factors. Surgery is recommended if symptoms are present, and the procedure type depends on patient factors, degree of instability, anomalous bony anatomy, and reduction results to relieve cord compression. Most commonly, posterior instrumented fusion is used. However, further research is required to determine the strength of evaluation methods, create standardized guidelines for evaluation and surgical treatment, and investigate the long-term results of different surgical techniques.

Impaired neurogenesis with reactive astrocytosis in the hippocampus in a porcine model of acquired hydrocephalus.

BACKGROUND: Hydrocephalus is a neurological disease with an incidence of 0.3-0.7 per 1000 live births in the United States. Ventriculomegaly, periventricular white matter alterations, inflammation, and gliosis are among the neuropathologies associated with this disease. We hypothesized that hippocampus structure and subgranular zone neurogenesis are altered in untreated hydrocephalus and correlate with recognition memory deficits. METHODS: Hydrocephalus was induced by intracisternal kaolin injections in domestic juvenile pigs (43.6 ± 9.8 days). Age-matched sham controls received similar saline injections. MRI was performed to measure ventricular volume, and/or hippocampal and perirhinal sizes at 14 ± 4 days and 36 ± 8 days post-induction. Recognition memory was assessed one week before and after kaolin induction. Histology and immunohistochemistry in the hippocampus were performed at sacrifice. RESULTS: The hippocampal width and the perirhinal cortex thickness were decreased (p < 0.05) in hydrocephalic pigs 14 ± 4 days post-induction. At sacrifice (36 ± 8 days post-induction), significant expansion of the cerebral ventricles was detected (p = 0.005) in hydrocephalic pigs compared with sham controls. The area of the dorsal hippocampus exhibited a reduction (p = 0.035) of 23.4% in the hydrocephalic pigs at sacrifice. Likewise, in hydrocephalic pigs, the percentages of neuronal precursor cells (doublecortin+ cells) and neurons decreased (p < 0.01) by 32.35%, and 19.74%, respectively, in the subgranular zone of the dorsal hippocampus. The percentage of reactive astrocytes (vimentin+) was increased (p = 0.041) by 48.7%. In contrast, microglial cells were found to decrease (p = 0.014) by 55.74% in the dorsal hippocampus in hydrocephalic pigs. There was no difference in the recognition index, a summative measure of learning and memory, one week before and after the induction of hydrocephalus. CONCLUSION: In untreated juvenile pigs, acquired hydrocephalus caused morphological alterations, reduced neurogenesis, and increased reactive astrocytosis in the hippocampus and perirhinal cortex.

A standardized infection prevention bundle for reduction of CSF shunt infections in adult ventriculoperitoneal shunt surgery performed without antibiotic-impregnated catheters.

OBJECTIVE: Ventriculoperitoneal (VP) shunt insertion and revision surgeries are some of the most common procedures that are performed by neurosurgeons. Shunt infections within the adult population are associated with significant morbidity and mortality and rates remain high. The objective of the current study was to use quality improvement (QI) methodology to create a standardized infection prevention bundle aimed at reducing the rate of shunt infections. METHODS: A prospective, single-center, single-surgeon QI study was undertaken. Patients were included if they were 18 years of age or older and were undergoing a VP shunt insertion or revision. The primary outcome of the study was the development of a shunt-related surgical site infection, within 1 year of surgery, as defined according to the Canadian Nosocomial Infection Surveillance Program guidelines. There was no standardized protocol prior to July 2013. A bundle coined as the Calgary Adult Shunt Infection Prevention Protocol (CASIPP) was implemented on July 1, 2013, and updated on July 1, 2015, when 2% chlorhexidine gluconate in 70% isopropyl alcohol replaced povidone-iodine for preoperative skin antisepsis. Protocol compliance was regularly monitored using a standardized process. No antibiotic-impregnated catheters were used. RESULTS: A total of 621 consecutive VP shunt insertions and revisions were included in the study. The rate of shunt infection was 5.8% during the period in which there was no standardized shunt protocol. After the implementation of the CASIPP the infection rate decreased to 4.0%, and after introduction of the chlorhexidine/alcohol skin antisepsis, the infection rate was 0% in 379 consecutive procedures (p < 0.0001). Multivariable logistic regression analysis demonstrated that the use of chlorhexidine/alcohol with CASIPP was associated with a significant reduction in the odds of developing a shunt infection (OR 0.032, 95% CI 0-0.19, p = 0.0005). CONCLUSIONS: The implementation of a standardized shunt infection prevention bundle within the adult population, without the use of antibiotic-impregnated catheters, significantly reduced the rate of shunt infections which was sustained over many years. The use of 2% chlorhexidine gluconate in 70% isopropyl alcohol for preoperative antisepsis may have played a significant role. Multicenter studies should be completed to verify the effectiveness of the authors' protocol.

Neuronavigation and Laparoscopy Guided Ventriculoperitoneal Shunt Insertion for the Treatment of Hydrocephalus.

Hydrocephalus is a common adult neurosurgical condition typically requiring treatment with a cerebrospinal fluid (CSF) shunt, of which the ventriculoperitoneal (VP) shunt is the most common type. Unfortunately, the failure rates of VP shunts are alarmingly high, with up to 50% of patients requiring revision surgery within 2 years. VP shunt failure may occur due to infection, or catheter mispositioning, migration, and occlusion. We undertook a joint neurosurgery and general surgery collaboration in a 7-year prospective non-randomized consecutive quality improvement cohort study to reduce the rates of ventriculoperitoneal (VP) shunt failures in 224 adult patients at a tertiary care institution. The initiative combined the use of electromagnetic stereotactic neuronavigation to guide the placement of the proximal catheter and laparoscopy to place the distal catheter under direct visualization. With laparoscopic assistance, the distal catheter was anchored through a small hole created in the falciform ligament and placed into the right retrohepatic space, free from the omentum, adhesions, or bowel that might obstruct the catheter tip. The surgeries were performed using a shunt infection prevention protocol to reduce the risk of shunt infections. Here, we present an intraoperative video of the surgical procedure. Compliance with shunt infection reduction strategies and the combined utilization of neuronavigation and laparoscopy techniques in adult VP shunt surgery resulted in a 44% reduction in the risk of overall shunt failure. The significant positive impact with regard to shunt-failure-free patient outcomes among patients who underwent VP shunt surgery using this strategy underscores the value associated with the use of these modern intraoperative techniques and cross-specialty collaboration during VP shunt surgery.

Clinical outcomes in pediatric hydrocephalus patients treated with endoscopic third ventriculostomy and choroid plexus cauterization: a systematic review and meta-analysis.

OBJECTIVE: Endoscopic third ventriculostomy and choroid plexus cauterization (ETV+CPC) is a novel procedure for infant hydrocephalus that was developed in sub-Saharan Africa to mitigate the risks associated with permanent implanted shunt hardware. This study summarizes the hydrocephalus literature surrounding the ETV+CPC intraoperative abandonment rate, perioperative mortality rate, cerebrospinal fluid infection rate, and failure rate. METHODS: This systematic review and meta-analysis followed a prespecified protocol and abides by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search strategy using MEDLINE, EMBASE, PsychInfo, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Scopus, and Web of Science was conducted from database inception to October 2019. Studies included controlled trials, cohort studies, and case-control studies of patients with hydrocephalus younger than 18 years of age treated with ETV+CPC. Pooled estimates were calculated using DerSimonian and Laird random-effects modeling, and the significance of subgroup analyses was tested using meta-regression. The quality of the pooled outcomes was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: After screening and reviewing 12,321 citations, the authors found 16 articles that met the inclusion criteria. The pooled estimate for the ETV+CPC failure rate was 0.44 (95% CI 0.37-0.51). Subgroup analysis by geographic income level showed statistical significance (p < 0.01), with lower-middle-income countries having a lower failure rate (0.32, 95% CI 0.28-0.36) than high-income countries (0.53, 95% CI 0.47-0.60). No difference in failure rate was found between hydrocephalus etiology (p = 0.09) or definition of failure (p = 0.24). The pooled estimate for perioperative mortality rate (n = 7 studies) was 0.001 (95% CI 0.00-0.004), the intraoperative abandonment rate (n = 5 studies) was 0.04 (95% CI 0.01-0.08), and the postoperative CSF infection rate (n = 5 studies) was 0.0004 (95% CI 0.00-0.003). All pooled outcomes were found to be low-quality evidence. CONCLUSIONS: This systematic review and meta-analysis provides the most comprehensive pooled estimate for the ETV+CPC failure rate to date and demonstrates, for the first time, a statistically significant difference in failure rate by geographic income level. It also provides the first reported pooled estimates for the risk of ETV+CPC perioperative mortality, intraoperative abandonment, and CSF infection. The low quality of this evidence highlights the need for further research to improve the understanding of these critical clinical outcomes and their relevant explanatory variables and thus to appreciate which patients may benefit most from an ETV+CPC. Systematic review registration no.: CRD42020160149 (https://www.crd.york.ac.uk/prospero/).

Acquired hydrocephalus is associated with neuroinflammation, progenitor loss, and cellular changes in the subventricular zone and periventricular white matter.

BACKGROUND: Hydrocephalus is a neurological disease with an incidence of 80-125 per 100,000 births in the United States. Neuropathology comprises ventriculomegaly, periventricular white matter (PVWM) alterations, inflammation, and gliosis. We hypothesized that hydrocephalus in a pig model is associated with subventricular and PVWM cellular alterations and neuroinflammation that could mimic the neuropathology described in hydrocephalic infants. METHODS: Hydrocephalus was induced by intracisternal kaolin injections in 35-day old female pigs (n = 7 for tissue analysis, n = 10 for CSF analysis). Age-matched sham controls received saline injections (n = 6). After 19-40 days, MRI scanning was performed to measure the ventricular volume. Stem cell proliferation was studied in the Subventricular Zone (SVZ), and cell death and oligodendrocytes were examined in the PVWM. The neuroinflammatory reaction was studied by quantifying astrocytes and microglial cells in the PVWM, and inflammatory cytokines in the CSF. RESULTS: The expansion of the ventricles was especially pronounced in the body of the lateral ventricle, where ependymal disruption occurred. PVWM showed a 44% increase in cell death and a 67% reduction of oligodendrocytes. In the SVZ, the number of proliferative cells and oligodendrocyte decreased by 75% and 57% respectively. The decrease of the SVZ area correlated significantly with ventricular volume increase. Neuroinflammation occurred in the hydrocephalic pigs with a significant increase of astrocytes and microglia in the PVWM, and high levels of inflammatory interleukins IL-6 and IL-8 in the CSF. CONCLUSION: The induction of acquired hydrocephalus produced alterations in the PVWM, reduced cell proliferation in the SVZ, and neuroinflammation.

Reducing the risks of proximal and distal shunt failure in adult hydrocephalus: a shunt outcomes quality improvement study.

OBJECTIVE: Patient outcomes of ventriculoperitoneal (VP) shunt surgery, the mainstay treatment for hydrocephalus in adults, are poor because of high shunt failure rates. The use of neuronavigation or laparoscopy can reduce the risks of proximal or distal shunt catheter failure, respectively, but has less independent effect on overall shunt failures. No adult studies to date have combined both approaches in the setting of a shunt infection prevention protocol to reduce shunt failure. The goal of this study was to determine whether combining neuronavigation and laparoscopy with a shunt infection prevention strategy would reduce the incidence of shunt failures in adult hydrocephalic patients. METHODS: Adult patients (age ≥ 18 years) undergoing VP shunt surgery at a tertiary care institution prior to (pre-Shunt Outcomes [ShOut]) and after (post-ShOut) the start of a prospective continuous quality improvement (QI) study were compared. Pre-ShOut patients had their proximal and distal catheters placed under conventional freehand approaches. Post-ShOut patients had their shunts inserted with neuronavigational and laparoscopy assistance in placing the distal catheter in the perihepatic space (falciform technique). A shunt infection reduction protocol had been instituted 1.5 years prior to the start of the QI initiative. The primary outcome of interest was the incidence of shunt failure (including infection) confirmed by standardized criteria indicating shunt revision surgery. RESULTS: There were 244 (115 pre-ShOut and 129 post-ShOut) patients observed over 7 years. With a background of shunt infection prophylaxis, combined neuronavigation and laparoscopy was associated with a reduction in overall shunt failure rates from 37% to 14%, 45% to 22%, and 51% to 29% at 1, 2, and 3 years, respectively (HR 0.44, p < 0.001). Shunt infection rates decreased from 8% in the pre-ShOut group to 0% in the post-ShOut group. There were no proximal catheter failures in the post-ShOut group. The 2-year rates of distal catheter failure were 42% versus 20% in the pre- and post-ShOut groups, respectively (p < 0.001). CONCLUSIONS: Introducing a shunt infection prevention protocol, placing the proximal catheter under neuronavigation, and placing the peritoneal catheter in the perihepatic space by using the falciform technique led to decreased rates of infection, distal shunt failure, and overall shunt failure.

Biochemical profile of human infant cerebrospinal fluid in intraventricular hemorrhage and post-hemorrhagic hydrocephalus of prematurity.

BACKGROUND: Intraventricular hemorrhage (IVH) and post-hemorrhagic hydrocephalus (PHH) have a complex pathophysiology involving inflammatory response, ventricular zone and cell-cell junction disruption, and choroid-plexus (ChP) hypersecretion. Increased cerebrospinal fluid (CSF) cytokines, extracellular matrix proteins, and blood metabolites have been noted in IVH/PHH, but osmolality and electrolyte disturbances have not been evaluated in human infants with these conditions. We hypothesized that CSF total protein, osmolality, electrolytes, and immune cells increase in PHH. METHODS: CSF samples were obtained from lumbar punctures of control infants and infants with IVH prior to the development of PHH and any neurosurgical intervention. Osmolality, total protein, and electrolytes were measured in 52 infants (18 controls, 10 low grade (LG) IVH, 13 high grade (HG) IVH, and 11 PHH). Serum electrolyte concentrations, and CSF and serum cell counts within 1-day of clinical sampling were obtained from clinical charts. Frontal occipital horn ratio (FOR) was measured for estimating the degree of ventriculomegaly. Dunn or Tukey's post-test ANOVA analysis were used for pair-wise comparisons. RESULTS: CSF osmolality, sodium, potassium, and chloride were elevated in PHH compared to control (p = 0.012 - < 0.0001), LGIVH (p = 0.023 - < 0.0001), and HGIVH (p = 0.015 - 0.0003), while magnesium and calcium levels were higher compared to control (p = 0.031) and LGIVH (p = 0.041). CSF total protein was higher in both HGIVH and PHH compared to control (p = 0.0009 and 0.0006 respectively) and LGIVH (p = 0.034 and 0.028 respectively). These differences were not reflected in serum electrolyte concentrations nor calculated osmolality across the groups. However, quantitatively, CSF sodium and chloride contributed 86% of CSF osmolality change between control and PHH; and CSF osmolality positively correlated with CSF sodium (r, p = 0.55,0.0015), potassium (r, p = 0.51,0.0041), chloride (r, p = 0.60,0.0004), but not total protein across the entire patient cohort. CSF total cells (p = 0.012), total nucleated cells (p = 0.0005), and percent monocyte (p = 0.016) were elevated in PHH compared to control. Serum white blood cell count increased in PHH compared to control (p = 0.042) but there were no differences in serum cell differential across groups. CSF total nucleated cells also positively correlated with CSF osmolality, sodium, potassium, and total protein (p = 0.025 - 0.0008) in the whole cohort. CONCLUSIONS: CSF osmolality increased in PHH, largely driven by electrolyte changes rather than protein levels. However, serum electrolytes levels were unchanged across groups. CSF osmolality and electrolyte changes were correlated with CSF total nucleated cells which were also increased in PHH, further suggesting PHH is a neuro-inflammatory condition.

Microstructural Periventricular White Matter Injury in Post-Hemorrhagic Ventricular Dilatation.

BACKGROUND AND OBJECTIVES: The neurological deficits of neonatal post-hemorrhagic hydrocephalus (PHH) have been linked to periventricular white matter injury. To improve understanding of PHH-related injury, diffusion basis spectrum imaging (DBSI) was applied in neonates, modeling axonal and myelin integrity, fiber density, and extra-fiber pathologies. Objectives included characterizing DBSI measures in periventricular tracts, associating measures with ventricular size, and examining MRI findings in the context of post-mortem white matter histology from similar cases. METHODS: A prospective cohort of infants born very preterm underwent term equivalent MRI, including infants with PHH, high-grade intraventricular hemorrhage without hydrocephalus (IVH), and controls (VPT). DBSI metrics extracted from the corpus callosum, corticospinal tracts, and optic radiations included fiber axial diffusivity, fiber radial diffusivity, fiber fractional anisotropy, fiber fraction (fiber density), restricted fractions (cellular infiltration), and non-restricted fractions (vasogenic edema). Measures were compared across groups and correlated with ventricular size. Corpus callosum postmortem immunohistochemistry in infants with and without PHH assessed intra- and extra-fiber pathologies. RESULTS: Ninety-five infants born very preterm were assessed (68 VPT, 15 IVH, 12 PHH). Infants with PHH had the most severe white matter abnormalities and there were no consistent differences in measures between IVH and VPT groups. Key tract-specific white matter injury patterns in PHH included reduced fiber fraction in the setting of axonal and/or myelin injury, increased cellular infiltration, vasogenic edema, and inflammation. Specifically, measures of axonal injury were highest in the corpus callosum; both axonal and myelin injury were observed in the corticospinal tracts; and axonal and myelin integrity were preserved in the setting of increased extra-fiber cellular infiltration and edema in the optic radiations. Increasing ventricular size correlated with worse DBSI metrics across groups. On histology, infants with PHH had high cellularity, variable cytoplasmic vacuolation, and low synaptophysin marker intensity. DISCUSSION: PHH was associated with diffuse white matter injury, including tract-specific patterns of axonal and myelin injury, fiber loss, cellular infiltration, and inflammation. Larger ventricular size was associated with greater disruption. Postmortem immunohistochemistry confirmed MRI findings. These results demonstrate DBSI provides an innovative approach extending beyond conventional diffusion MRI for investigating neuropathological effects of PHH on neonatal brain development.

A novel model of acquired hydrocephalus for evaluation of neurosurgical treatments.

BACKGROUND: Many animal models have been used to study the pathophysiology of hydrocephalus; most of these have been rodent models whose lissencephalic cerebral cortex may not respond to ventriculomegaly in the same way as gyrencephalic species and whose size is not amenable to evaluation of clinically relevant neurosurgical treatments. Fewer models of hydrocephalus in gyrencephalic species have been used; thus, we have expanded upon a porcine model of hydrocephalus in juvenile pigs and used it to explore surgical treatment methods. METHODS: Acquired hydrocephalus was induced in 33-41-day old pigs by percutaneous intracisternal injections of kaolin (n = 17). Controls consisted of sham saline-injected (n = 6) and intact (n = 4) animals. Magnetic resonance imaging (MRI) was employed to evaluate ventriculomegaly at 11-42 days post-kaolin and to plan the surgical implantation of ventriculoperitoneal shunts at 14-38-days post-kaolin. Behavioral and neurological status were assessed. RESULTS: Bilateral ventriculomegaly occurred post-induction in all regions of the cerebral ventricles, with prominent CSF flow voids in the third ventricle, foramina of Monro, and cerebral aqueduct. Kaolin deposits formed a solid cast in the basal cisterns but the cisterna magna was patent. In 17 untreated hydrocephalic animals. Mean total ventricular volume was 8898 ± 5917 SD mm3 at 11-43 days of age, which was significantly larger than the baseline values of 2251 ± 194 SD mm3 for 6 sham controls aged 45-55 days, (p < 0.001). Past the post-induction recovery period, untreated pigs were asymptomatic despite exhibiting mild-moderate ventriculomegaly. Three out of 4 shunted animals showed a reduction in ventricular volume after 20-30 days of treatment, however some developed ataxia and lethargy, from putative shunt malfunction. CONCLUSIONS: Kaolin induction of acquired hydrocephalus in juvenile pigs produced an in vivo model that is highly translational, allowing systematic studies of the pathophysiology and clinical treatment of hydrocephalus.

The impact of hypoxia on blood-brain, blood-CSF, and CSF-brain barriers.

The blood-brain barrier (BBB), blood-cerebrospinal fluid (CSF) barrier (BCSFB), and CSF-brain barriers (CSFBB) are highly regulated barriers in the central nervous system comprising complex multicellular structures that separate nerves and glia from blood and CSF, respectively. Barrier damage has been implicated in the pathophysiology of diverse hypoxia-related neurological conditions, including stroke, multiple sclerosis, hydrocephalus, and high-altitude cerebral edema. Much is known about the damage to the BBB in response to hypoxia, but much less is known about the BCSFB and CSFBB. Yet, it is known that these other barriers are implicated in damage after hypoxia or inflammation. In the 1950s, it was shown that the rate of radionucleated human serum albumin passage from plasma to CSF was five times higher during hypoxic than normoxic conditions in dogs, due to BCSFB disruption. Severe hypoxia due to administration of the bacterial toxin lipopolysaccharide is associated with disruption of the CSFBB. This review discusses the anatomy of the BBB, BCSFB, and CSFBB and the impact of hypoxia and associated inflammation on the regulation of those barriers.

Immune activation during Paenibacillus brain infection in African infants with frequent cytomegalovirus co-infection.

Inflammation during neonatal brain infections leads to significant secondary sequelae such as hydrocephalus, which often follows neonatal sepsis in the developing world. In 100 African hydrocephalic infants we identified the biological pathways that account for this response. The dominant bacterial pathogen was a Paenibacillus species, with frequent cytomegalovirus co-infection. A proteogenomic strategy was employed to confirm host immune response to Paenibacillus and to define the interplay within the host immune response network. Immune activation emphasized neuroinflammation, oxidative stress reaction, and extracellular matrix organization. The innate immune system response included neutrophil activity, signaling via IL-4, IL-12, IL-13, interferon, and Jak/STAT pathways. Platelet-activating factors and factors involved with microbe recognition such as Class I MHC antigen-presenting complex were also increased. Evidence suggests that dysregulated neuroinflammation propagates inflammatory hydrocephalus, and these pathways are potential targets for adjunctive treatments to reduce the hazards of neuroinflammation and risk of hydrocephalus following neonatal sepsis.

Primary and metastatic glioblastoma of the spine in the pediatric population: a systematic review.

Pediatric glioblastoma multiforme (GBM) involving the spine is an aggressive tumor with a poor quality of life for patients. Despite this, there is only a limited number of reports describing the outcomes of pediatric spinal GBMs, both as primary spinal GBMs and metastases from an intracranial tumor. Here, we performed an individual patient meta-analysis to characterize factors affecting prognosis of pediatric spinal GBM. MEDLINE, Embase, and the Cochrane databases were searched for published studies on GBMs involving the spine in pediatric patients (age ≤ 21 years old). Factors associated with the survival were assessed with multi-factor ANOVAs, Cox hazard regression, and Kaplan-Meier analyses. We extracted data on 61 patients with spinal GBM from 40 studies that met inclusion criteria. Median survival was significantly longer in the primary spinal GBM compared that those with metastatic GBM (11 vs 3 months, p < 0.001). However, median survival of metastatic GBM patients was 10 months following diagnosis of their primary brain tumor, which was not different from that of primary spinal GBM patients (p = 0.457). Among primary spinal GBM patients, chemotherapy (hazard ratio (HR) = 0.255 [0.106-0.615], p = 0.013) and extent of resection (HR = 0.582 [0.374-0.905], p = 0.016) conferred a significant survival benefit. Younger age (less than 14 years) was associated with longer survival in patients treated with chemotherapy than those who did not undergo chemotherapy (ß = - 1.12, 95% CI [- 2.20, - 0.03], p < 0.05). In conclusion, survival after presentation of metastases from intracranial GBM is poor in the pediatric population. In patients with metastatic GBM, chemotherapy may have provided the most benefit in young patients, and its efficacy might have an association with extent of surgical resection.

Natural History, Treatment Outcomes and Quality of Life in Idiopathic Normal Pressure Hydrocephalus (iNPH).

BACKGROUND: The natural history and treatment outcomes in adult patients with hydrocephalus is a broad and heterogeneous topic that encompasses the natural history of the various subtypes of adult hydrocephalus with or without treatment; their surgical operative results, including symptom improvements, treatment failure, short- and long-term complications, and reoperations; and morbidity, mortality, and patient-centered health-related quality of life (HRQoL). OBJECTIVE, METHODS, AND MATERIALS: The objective of this review is to present a current update on the natural history and treatment outcomes, including QoL, for adults with hydrocephalus with a focus on patients with idiopathic normal pressure hydrocephalus (iNPH). A nonsystematic review of relevant literature was summarized. RESULTS AND CONCLUSIONS: The natural history for untreated patients with iNPH is poor, with both increased mortality and morbidity. It is strongly recommended that practitioners follow established guidelines to select patients with suspected iNPH while using objective measures of gait, balance, and cognition for consideration of treatment with a CSF shunt. Other factors such as patient-related medical comorbidities or frailty may need to be factored into the decision-making process before surgical treatment is offered. As a rule, failure to select patients based on the identified guidelines will result in a significantly lower positive response to treatment with a CSF shunt. Over 90% of iNPH patients who undergo CSF-shunt treatment demonstrate symptomatic relief after surgery, and long-term studies have shown that in most patients, the clinical improvements are long-lasting, with over 70% demonstrating improvement longer than 6 years after treatment. There is no evidence to support the routine use of endoscopic third ventriculostomy (ETV) to treat patients with iNPH. There is limited data regarding HRQoL in patients with iNPH. In addition to objective measures of outcomes focused on gait and cognition, it is equally important for future studies to assess patient-centered subjective measures of HRQoL.