Ventricular catheter tissue obstruction and shunt malfunction in 9 hydrocephalus etiologies.

OBJECTIVE: Hydrocephalus is a neurological disorder with an incidence of 80-125 per 100,000 births in the United States. The most common treatment, ventricular shunting, has a failure rate of up to 85% within 10 years of placement. The authors aimed to analyze the association between ventricular catheter (VC) tissue obstructions and shunt malfunction for each hydrocephalus etiology. METHODS: Patient information was collected from 5 hospitals and entered into a REDCap (Research Electronic Data Capture) database by hydrocephalus etiology. The hardware samples were fixed, and each VC tip drainage hole was classified by tissue obstruction after macroscopic analysis. Shunt malfunction data, including shunt revision rate, time to failure, and age at surgery, were correlated with the degree of tissue obstruction in VCs for each etiology. RESULTS: Posthemorrhagic hydrocephalus was the most common etiology (48.9% of total cases). Proximal catheter obstruction was the most frequent cause of hardware removal (90.4%). Myelomeningocele (44% ± 29%), other congenital etiologies (48% ± 40%), hydrocephalus with brain tumors (45% ± 35%), and posthemorrhagic hydrocephalus (41% ± 35%) showed tissue aggregates in more than 40% of the VC holes. A total of 76.8% of samples removed because of symptoms of obstruction showed cellular or tissue aggregates. No conclusive etiological associations were detected when correlating the percentage of holes with tissue for each VC and age at surgery, shunt revision rates, or time between shunt implantation and removal. CONCLUSIONS: The proximal VC obstruction was accompanied by tissue aggregates in 76.8% of cases. However, the presence of tissue in the VC did not seem to be associated with hydrocephalus etiology.

Exploration of clinical predictors of the degree of ventricular catheter obstruction: a multicenter retrospective study.

OBJECTIVE: The aim of this study was to explore how clinical factors, including the number of lifetime revision surgeries and the duration of implantation, affect the degree of obstruction and failure rates of ventricular catheters (VCs) used to manage hydrocephalus. METHODS: A total of 343 VCs and their associated clinical data, including patient demographics, medical history, and surgical details, were collected from 5 centers and used for this analysis. Each VC was classified by the degree of obstruction after macroscopic analysis. Univariate, multivariate, and binned analyses were conducted to test for associations between clinical data and degree of VC obstruction. RESULTS: VCs from patients with 0 to 2 lifetime revisions had a larger proportion of VC holes obstructed than VCs from patients with 10 or more revisions (p = 0.0484). VCs implanted for less than 3 months had fewer obstructed holes with protruding tissue aggregates than VCs implanted for 13 months or longer (p = 0.0225). Neither duration of implantation nor the number of lifetime revisions was a significant predictor of the degree of VC obstruction in the regression models. In the multinomial regression model, contact of the VCs with the ventricular wall robustly predicted the overall obstruction status of a VC (p = 0.005). In the mixed-effects model, the age of the patient at their first surgery emerged as a significant predictor of obstruction by protruding tissue aggregates (p = 0.002). VCs implanted through the parietal entry site were associated with more holes with nonobstructive growth and fewer empty holes than VCs implanted via other approaches (p = 0.001). CONCLUSIONS: The number of lifetime revisions and duration of implantation are correlated with the degree of VC obstruction but do not predict it. Contact of the VC with the ventricular wall and the age of the patient at their first surgery are predictors of the degree of VC obstruction, while the entry site of the VC correlates with it.

Promoting regeneration while blocking cell death preserves motor neuron function in a model of ALS.

Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disease of motor neurons with very few treatment options. We had previously found that motor neuron degeneration in a mouse model of ALS can be delayed by deleting the axon damage sensor MAP3K12 or dual leucine zipper kinase (DLK). However, DLK is also involved in axon regeneration, prompting us to ask whether combining DLK deletion with a way to promote axon regeneration would result in greater motor neuron protection. To achieve this, we used a mouse line that constitutively expresses ATF3, a master regulator of regeneration in neurons. Although there is precedence for each individual strategy in the SOD1G93A mouse model of ALS, these have not previously been combined. By several lines of evidence including motor neuron electrophysiology, histology and behaviour, we observed a powerful synergy when combining DLK deletion with ATF3 expression. The combinatorial strategy resulted in significant protection of motor neurons with fewer undergoing cell death, reduced axon degeneration and preservation of motor function and connectivity to muscle. This study provides a demonstration of the power of combinatorial therapy to treat neurodegenerative disease.

The effect of A1 and A2 reactive astrocyte expression on hydrocephalus shunt failure.

BACKGROUND: The composition of tissue obstructing neuroprosthetic devices is largely composed of inflammatory cells with a significant astrocyte component. In a first-of-its-kind study, we profile the astrocyte phenotypes present on hydrocephalus shunts. METHODS: qPCR and RNA in-situ hybridization were used to quantify pro-inflammatory (A1) and anti-inflammatory (A2) reactive astrocyte phenotypes by analyzing C3 and EMP1 genes, respectively. Additionally, CSF cytokine levels were quantified using ELISA. In an in vitro model of astrocyte growth on shunts, different cytokines were used to prevent the activation of resting astrocytes into the A1 and A2 phenotypes. Obstructed and non-obstructed shunts were characterized based on the degree of actual tissue blockage on the shunt surface instead of clinical diagnosis. RESULTS: The results showed a heterogeneous population of A1 and A2 reactive astrocytes on the shunts with obstructed shunts having a significantly higher proportion of A2 astrocytes compared to non-obstructed shunts. In addition, the pro-A2 cytokine IL-6 inducing proliferation of astrocytes was found at higher concentrations among CSF from obstructed samples. Consequently, in the in vitro model of astrocyte growth on shunts, cytokine neutralizing antibodies were used to prevent activation of resting astrocytes into the A1 and A2 phenotypes which resulted in a significant reduction in both A1 and A2 growth. CONCLUSIONS: Therefore, targeting cytokines involved with astrocyte A1 and A2 activation is a promising intervention aimed to prevent shunt obstruction.

Women in Neurosurgery: A PRISMA-Compliant Systematic Review of Where We Stand and a Pilot Study on How to Move Forward.

BACKGROUND: Surgical specialties struggle to recruit women. In this study, the authors performed a systematic review to describe progress of women in neurosurgery and highlight areas where further research is needed. METHODS: PubMed, Embase, and Cochrane Library were queried with "women in neurosurgery" OR "female neurosurgeon," and publications with empiric research were included. Bias was assessed on the basis of study designs. RESULTS: We found 127 papers, and 36 met inclusion criteria. Much of this research is recent-85% has been published within the past 3 years. These papers detail differences between genders and examine possible causes, but they do not test interventions to remedy inequities. The authors designed an intervention focusing on medical students' perceptions of gender issues within neurosurgery. A seminar was designed with 2 objectives: inform medical students about changes within neurosurgery and introduce them to a female neurosurgery attending who could serve as a potential future mentor. Student attitudes were assessed before and after the seminar by survey. Fourteen students completed both surveys: 10 females and 4 males. CONCLUSIONS: The 1-hour seminar significantly reduced the mean perceived difficulty to enter neurosurgery from 4.4 to 4.1 (P = 0.014); additionally, the mean perceived additional difficulty for career advancement faced by women in neurosurgery decreased from 3.6 to 2.8 (P = 0.026). Much research has gone into documenting the advancement and potential impediments for women in neurosurgery. Less research has tested solutions. Our pilot was small and susceptible to bias, but given that some results achieved significance, it merits more rigorous study.

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.

Biographies of international women leaders in neurosurgery.

We received so many biographies of women neurosurgery leaders for this issue that only a selection could be condensed here. In all of them, the essence of a leader shines through. Many are included as "first" of their country or color or other achievement. All of them are included as outstanding-in clinical, academic, and organized neurosurgery. Two defining features are tenacity and service. When faced with shocking discrimination, or numbing indifference, they ignored it or fought valiantly. When choosing their life's work, they chose service, often of the most neglected-those with pain, trauma, and disability. These women inspire and point the way to a time when the term "women leaders" as an exception is unnecessary.-Katharine J. Drummond, MD, on behalf of this month's topic editors.

Factors Impacting Hydrocephalus Incidence in Intracerebral Hemorrhage: A Retrospective Analysis.

OBJECTIVE: To test which intracerebral hemorrhage (ICH) characteristics impact incidence of hydrocephalus and characterize subsequent impact on outcomes. METHODS: A search of the electronic medical record of Sinai Grace Hospital between January 2009 and April 2018 using International Classification of Diseases, Ninth Revision and Tenth Revision codes for ICH identified 847 patients. After excluding patients with hemorrhagic conversion of stroke, subarachnoid hemorrhage, and traumatic hemorrhage, 560 patients remained for analysis. Generalized linear modeling was used to assess variance in modified Rankin Scale (mRS) score and length of stay. RESULTS: Incidence of hydrocephalus on arrival varied with ICH volume (P < 0.001), intraventricular hemorrhage (IVH) status (P < 0.001), bleed location (P < 0.001), and external ventricular drain (EVD) status (P < 0.001). An EVD was inserted in 47% of patients presenting with IVH (n = 102/217), while 4% of patients without IVH received an EVD (n = 14/343) (P < 0.001). Hemorrhage locations had different rates of EVD placement: thalamic 43%, basal ganglia 22%, cerebellar 28%, brainstem 21%, lobar 7% (P < 0.001). Shunt dependency did not vary between bleed locations (P = 0.072). Variance in mRS score was explained by IVH, bleed location, hydrocephalus on arrival, and ICH volumes. In particular, cerebellar hemorrhage location was associated with better outcomes (mean discharge mRS score of 3.3 vs. 3.9, P < 0.001). CONCLUSIONS: Bleed characteristics affect incidence of hydrocephalus on admission, rates of long-term shunt dependency, and outcomes. Hemorrhage location did not predict shunt dependency; however, it did predict outcomes. Specifically, cerebellar ICH was associated with a better discharge mRS score.

Investigation of ventriculoperitoneal shunt disconnection for hydrocephalus treatment.

OBJECTIVE: This investigation is aimed at gaining a better understanding of the factors that lead to mechanical failure of shunts used for the treatment of hydrocephalus, including shunt catheter-valve disconnection and shunt catheter fracture. METHODS: To determine the root cause of mechanical failure, the authors created a benchtop mechanical model to mimic mechanical stressors on a shunt system. To test shunt fracture, cyclical loading on the catheter-valve connection site was tested with the shunt catheter held perpendicular to the valve. Standard methods were used to secure the catheter and valves with Nurolon. These commercial systems were compared to integrated catheters and valves (manufactured as one unit). To test complete separation/disconnection of the shunt catheter and valve, a parallel displacement test was conducted using both Nurolon and silk sutures. Finally, the stiffness of the catheters was assessed. All mechanical investigations were conducted on shunts from two major shunt companies, assigned as either company A or company B. RESULTS: Cyclical loading experiments found that shunts from company B fractured after a mean of 4936 ± 1725 cycles (95% CI 2990-6890 cycles), while those of company A had not failed after 8000 cycles. The study of parallel displacement indicated complete disconnection of company B's shunt catheter-valve combination using Nurolon sutures after being stretched an average 32 ± 5.68 mm (95% CI 25.6-38.4 mm), whereas company A's did not separate using either silk or Nurolon sutures. During the stiffness experiments, the catheters of company B had statistically significantly higher stiffness of 13.23 ± 0.15 N compared to those of company A, with 6.16 ± 0.29 N (p < 0.001). CONCLUSIONS: Mechanical shunt failure from shunt catheter-valve disconnection or fracture is a significant cause of shunt failure. This study demonstrates, for the first time, a correlation between shunt catheters that are less mechanically stiff and those that are less likely to disconnect from the valve when outstretched and are also less likely to tear when held at an angle from the valve outlet. The authors propose an intervention to the standard of care wherein less stiff catheters are trialed to reduce disconnection.

Characterization of a multicenter pediatric-hydrocephalus shunt biobank.

BACKGROUND: Pediatric hydrocephalus is a devastating and costly disease. The mainstay of treatment is still surgical shunting of cerebrospinal fluid (CSF). These shunts fail at a high rate and impose a significant burden on patients, their families and society. The relationship between clinical decision making and shunt failure is poorly understood and multifaceted, but catheter occlusion remains the most frequent cause of shunt complications. In order to investigate factors that affect shunt failure, we have established the Wayne State University (WSU) shunt biobank. METHODS: To date, four hospital centers have contributed various components of failed shunts and CSF from patients diagnosed with hydrocephalus before adulthood. The hardware samples are transported in paraformaldehyde and transferred to phosphate-buffered saline with sodium azide upon deposit into the biobank. Once in the bank, they are then available for study. Informed consent is obtained by the local center before corresponding clinical data are entered into a REDCap database. Data such as hydrocephalus etiology and details of shunt revision history. All data are entered under a coded identifier. RESULTS: 293 shunt samples were collected from 228 pediatric patients starting from May 2015 to September 2019. We saw a significant difference in the number of revisions per patient between centers (Kruskal-Wallis H test, p value < 0.001). The leading etiology at all centers was post-hemorrhagic hydrocephalus, a fisher's exact test showed there to be statistically significant differences in etiology between center (p = 0.01). Regression showed age (p < 0.01), race (p = 0.038) and hospital-center (p < 0.001) to explain significant variance in the number of revisions. Our model accounted for 31.9% of the variance in revisions. Generalized linear modeling showed hydrocephalus etiology (p < 0.001), age (p < 0.001), weight and physician (p < 0.001) to impact the number of ventricular obstructions. CONCLUSION: The retrospective analysis identified that differences exist between currently enrolled centers, although further work is needed before clinically actionable recommendations can be made. Moreover, the variables collected from this chart review explain a meaningful amount of variance in the number of revision surgeries. Future work will expand on the contribution of different site-specific and patient-specific factors to identify potential cause and effect relationships.

Dual leucine zipper kinase is required for mechanical allodynia and microgliosis after nerve injury.

Neuropathic pain resulting from nerve injury can become persistent and difficult to treat but the molecular signaling responsible for its development remains poorly described. Here, we identify the neuronal stress sensor dual leucine zipper kinase (DLK; Map3k12) as a key molecule controlling the maladaptive pathways that lead to pain following injury. Genetic or pharmacological inhibition of DLK reduces mechanical hypersensitivity in a mouse model of neuropathic pain. Furthermore, DLK inhibition also prevents the spinal cord microgliosis that results from nerve injury and arises distant from the injury site. These striking phenotypes result from the control by DLK of a transcriptional program in somatosensory neurons regulating the expression of numerous genes implicated in pain pathogenesis, including the immune gene Csf1. Thus, activation of DLK is an early event, or even the master regulator, controlling a wide variety of pathways downstream of nerve injury that ultimately lead to chronic pain.