Postoperative shunt failure following hemispherectomy in pediatric patients with pre-existing hydrocephalus.

OBJECTIVE: The risk of hydrocephalus following hemispherectomy for drug resistant epilepsy (DRE) remains high. Patients with pre-existing hydrocephalus pose a postoperative challenge, as maintaining existing shunt patency is necessary but lacks a clearly defined strategy. This study examines the incidence and predictors of shunt failure in pediatric hemispherectomy patients with pre-existing ventricular shunts. METHODS: We performed a retrospective chart review at our center to identify pediatric patients diagnosed with DRE who were treated with ventricular shunt prior to their first hemispherectomy surgery. Demographic and perioperative data were obtained including shunt history, hydrocephalus etiology, epilepsy duration, surgical technique, and postoperative outcomes. Univariate analysis was performed using Fisher's exact test and Pearson correlation, with Bonferroni correction to a = 0.00625 and a = 0.01, respectively. RESULTS: Five of nineteen (26.3%) patients identified with ventriculoperitoneal shunting prior to hemispherectomy experienced postoperative shunt malfunction. All 5 of these patients underwent at least 1 shunt revision prior to hemispherectomy, with a significant association between pre- and post-hemispherectomy shunt revisions. There was no significant association between post-hemispherectomy shunt failure and valve type, intraoperative shunt alteration, postoperative external ventricular drain placement, hemispherectomy revision, lateralization of shunt relative to resection, postoperative complications, or postoperative aseptic meningitis. There was no significant correlation between number of post-hemispherectomy shunt revisions and age at shunt placement, age at hemispherectomy, epilepsy duration, or shunt duration prior to hemispherectomy. CONCLUSIONS: Earlier shunt revision surgery may portend a subsequent need for shunt revision following hemispherectomy. These findings may guide neurosurgeons in counseling patients with pre-existing ventricular shunts prior to hemispherectomy surgery.

Predictive factors of hydrocephalus development in pediatric patients undergoing hemispherectomy for intractable epilepsy.

OBJECTIVE: Hemispherectomy surgery is an effective procedure for pediatric patients with intractable hemispheric epilepsy. Hydrocephalus is a well-documented complication of hemispherectomy contributing substantially to patient morbidity. Despite some clinical and operative factors demonstrating an association with hydrocephalus development, the true mechanism of disease is incompletely understood. The aim of this study was to investigate a range of clinical and surgical factors that may contribute to hydrocephalus to enhance understanding of the development of this complication and to aid the clinician in optimizing peri- and postoperative surgical management. METHODS: A retrospective chart review was conducted on all pediatric patients younger than 21 years who underwent hemispherectomy surgery at the Cleveland Clinic between 2002 and 2016. Data collected for each patient included general demographic information, neurological and surgical history, surgical technique, pathological analysis, presence and duration of perioperative CSF diversion, CSF laboratory values obtained while an external ventricular drain (EVD) was in place, length of hospital stay, postoperative aseptic meningitis, and in-hospital surgical complications (including perioperative stroke, hematoma formation, wound breakdown, and/or infection). Outcomes data included hemispherectomy revision and Engel grade at last follow-up (based on the Engel Epilepsy Surgery Outcome Scale). RESULTS: Data were collected for 204 pediatric patients who underwent hemispherectomy at the authors' institution. Twenty-eight patients (14%) developed hydrocephalus requiring CSF diversion. Of these 28 patients, 13 patients (46%) presented with hydrocephalus during the postoperative period (within 90 days), while the remaining 15 patients (54%) presented later (beyond 90 days after surgery). Multivariate analysis revealed postoperative aseptic meningitis (OR 7.0, p = 0.001), anatomical hemispherectomy surgical technique (OR 16.3 for functional/disconnective hemispherectomy and OR 7.6 for modified anatomical, p = 0.004), male sex (OR 4.2, p = 0.012), and surgical complications (OR 3.8, p = 0.031) were associated with an increased risk of hydrocephalus development, while seizure freedom (OR 0.3, p = 0.038) was associated with a decreased risk of hydrocephalus. CONCLUSIONS: Hydrocephalus remains a prominent complication following hemispherectomy, presenting both in the postoperative period and months to years after surgery. Aseptic meningitis, anatomical hemispherectomy surgical technique, male sex, and surgical complications show an association with an increased rate of hydrocephalus development while seizure freedom postsurgery is associated with a decreased risk of subsequent hydrocephalus. These findings speak to the multifactorial nature of hydrocephalus development and should be considered in the management of pediatric patients undergoing hemispherectomy for medically intractable epilepsy.

Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia.

Traumatic brain injury (TBI) can lead to significant neuropsychiatric problems and neurodegenerative pathologies, which develop and persist years after injury. Neuroinflammatory processes evolve over this same period. Therefore, we aimed to determine the contribution of microglia to neuropathology at acute [1 d postinjury (dpi)], subacute (7 dpi), and chronic (30 dpi) time points. Microglia were depleted with PLX5622, a CSF1R antagonist, before midline fluid percussion injury (FPI) in male mice and cortical neuropathology/inflammation was assessed using a neuropathology mRNA panel. Gene expression associated with inflammation and neuropathology were robustly increased acutely after injury (1 dpi) and the majority of this expression was microglia independent. At 7 and 30 dpi, however, microglial depletion reversed TBI-related expression of genes associated with inflammation, interferon signaling, and neuropathology. Myriad suppressed genes at subacute and chronic endpoints were attributed to neurons. To understand the relationship between microglia, neurons, and other glia, single-cell RNA sequencing was completed 7 dpi, a critical time point in the evolution from acute to chronic pathogenesis. Cortical microglia exhibited distinct TBI-associated clustering with increased type-1 interferon and neurodegenerative/damage-related genes. In cortical neurons, genes associated with dopamine signaling, long-term potentiation, calcium signaling, and synaptogenesis were suppressed. Microglial depletion reversed the majority of these neuronal alterations. Furthermore, there was reduced cortical dendritic complexity 7 dpi, reduced neuronal connectively 30 dpi, and cognitive impairment 30 dpi. All of these TBI-associated functional and behavioral impairments were prevented by microglial depletion. Collectively, these studies indicate that microglia promote persistent neuropathology and long-term functional impairments in neuronal homeostasis after TBI.SIGNIFICANCE STATEMENT Millions of traumatic brain injuries (TBIs) occur in the United States alone each year. Survivors face elevated rates of cognitive and psychiatric complications long after the inciting injury. Recent studies of human brain injury link chronic neuroinflammation to adverse neurologic outcomes, suggesting that evolving inflammatory processes may be an opportunity for intervention. Here, we eliminate microglia to compare the effects of diffuse TBI on neurons in the presence and absence of microglia and microglia-mediated inflammation. In the absence of microglia, neurons do not undergo TBI-induced changes in gene transcription or structure. Microglial elimination prevented TBI-induced cognitive changes 30 d postinjury (dpi). Therefore, microglia have a critical role in disrupting neuronal homeostasis after TBI, particularly at subacute and chronic timepoints.

Comparison between midline and lateral fluid percussion injury in mice reveals prolonged but divergent cortical neuroinflammation.

Animal models are critical for determining the mechanisms mediating traumatic brain injury-induced (TBI) neuropathology. Fluid percussion injury (FPI) is a widely used model of brain injury typically applied either midline or parasagittally (lateral). Midline FPI induces a diffuse TBI, while lateral FPI induces both focal cortical injury (ipsilateral hemisphere) and diffuse injury (contralateral hemisphere). Nonetheless, discrete differences in neuroinflammation and neuropathology between these two versions of FPI remain unclear. The purpose of this study was to compare acute (4-72 h) and subacute (7 days) neuroinflammatory responses between midline and lateral FPI. Midline FPI resulted in longer righting reflex times than lateral FPI. At acute time points, the inflammatory responses to the two different injuries were similar. For instance, there was evidence of monocytes and cytokine mRNA expression in the brain with both injuries acutely. Midline FPI had the highest proportion of brain monocytes and highest IL-1ß/TNFα mRNA expression 24 h later. NanoString nCounter analysis 7 days post-injury revealed robust and prolonged expression of inflammatory-related genes in the cortex after midline FPI compared to lateral FPI; however, Iba-1 cortical immunoreactivity was increased with lateral FPI. Thus, midline and lateral FPI caused similar cortical neuroinflammatory responses acutely and mRNA expression of inflammatory genes was detectable in the brain 7 days later. The primary divergence was that inflammatory gene expression was greater and more diverse subacutely after midline FPI. These results provide novel insight to variations between midline and lateral FPI, which may recapitulate unique temporal pathogenesis.