Kristopher G. Hooten

Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disorder characterized by loss of motor neurons, resulting in paralysis and death. Multiple mechanisms of motor neuron injury have been implicated based upon the more than 20 different genetic causes of familial ALS. These inherited mutations compromise diverse motor neuron pathways leading to cell-autonomous injury. In the ALS transgenic mouse models, however, motor neurons do not die alone. Cell death is noncell-autonomous dependent upon a well orchestrated dialogue between motor neurons and surrounding glia and adaptive immune cells. The pathogenesis of ALS consists of 2 stages: an early neuroprotective stage and a later neurotoxic stage. During early phases of disease progression, the immune system is protective with glia and T cells, especially M2 macrophages/microglia, and T helper 2 cells and regulatory T cells, providing anti-inflammatory factors that sustain motor neuron viability. As the disease progresses and motor neuron injury accelerates, a second rapidly progressing phase develops, characterized by M1 macrophages/microglia, and proinflammatory T cells. In rapidly progressing ALS patients, as in transgenic mice, neuroprotective regulatory T cells are significantly decreased and neurotoxicity predominates. Our own therapeutic efforts are focused on modulating these neuroinflammatory pathways. This review will focus on the cellular players involved in neuroinflammation in ALS and current therapeutic strategies to enhance neuroprotection and suppress neurotoxicity with the goal of arresting the progressive and devastating nature of ALS.

Critical role of PI3K/Akt/GSK3β in motoneuron specification from human neural stem cells in response to FGF2 and EGF.

Fibroblast growth factor (FGF) and epidermal growth factor (EGF) are critical for the development of the nervous system. We previously discovered that FGF2 and EGF had opposite effects on motor neuron differentiation from human fetal neural stem cells (hNSCs), but the underlying mechanisms remain unclear. Here, we show that FGF2 and EGF differentially affect the temporal patterns of Akt and glycogen synthase kinase 3 beta (GSK3β) activation. High levels of phosphatidylinositol 3-kinase (PI3K)/Akt activation accompanied with GSK3β inactivation result in reduction of the motor neuron transcription factor HB9. Inhibition of PI3K/Akt by chemical inhibitors or RNA interference or overexpression of a constitutively active form of GSK3β enhances HB9 expression. Consequently, PI3K inhibition increases hNSCs differentiation into HB9+/microtubule-associated protein 2 (MAP2)+ motor neurons in vitro. More importantly, blocking PI3K not only enhances motor neuron differentiation from hNSCs grafted into the ventral horn of adult rat spinal cords, but also permits ectopic generation of motor neurons in the dorsal horn by overriding environmental influences. Our data suggest that FGF2 and EGF affect the motor neuron fate decision in hNSCs differently through a fine tuning of the PI3K/AKT/GSK3β pathway, and that manipulation of this pathway can enhance motor neuron generation.

The role of simulation in neurosurgery

PurposeIn an era of residency duty-hour restrictions, there has been a recent effort to implement simulation-based training methods in neurosurgery teaching institutions. Several surgical simulators have been developed, ranging from physical models to sophisticated virtual reality systems. To date, there is a paucity of information describing the clinical benefits of existing simulators and the assessment strategies to help implement them into neurosurgical curricula. Here, we present a systematic review of the current models of simulation and discuss the state-of-the-art and future directions for simulation in neurosurgery.MethodsRetrospective literature review.ResultsMultiple simulators have been developed for neurosurgical training, including those for minimally invasive procedures, vascular, skull base, pediatric, tumor resection, functional neurosurgery, and spine surgery. The pros and cons of existing systems are reviewed.ConclusionAdvances in imaging and computer technology have led to the development of different simulation models to complement traditional surgical training. Sophisticated virtual reality (VR) simulators with haptic feedback and impressive imaging technology have provided novel options for training in neurosurgery. Breakthrough training simulation using 3D printing technology holds promise for future simulation practice, proving high-fidelity patient-specific models to complement residency surgical learning.

Mixed Reality Ventriculostomy Simulation: Experience in Neurosurgical Residency

BACKGROUND: Medicine and surgery are turning toward simulation to improve on limited patient interaction during residency training. Many simulators today use virtual reality with augmented haptic feedback with little to no physical elements. In a collaborative effort, the University of Florida Department of Neurosurgery and the Center for Safety, Simulation & Advanced Learning Technologies created a novel “mixed” physical and virtual simulator to mimic the ventriculostomy procedure. The simulator contains all the physical components encountered for the procedure with superimposed 3-D virtual elements for the neuroanatomical structures. OBJECTIVE: To introduce the ventriculostomy simulator and its validation as a necessary training tool in neurosurgical residency. METHODS: We tested the simulator in more than 260 residents. An algorithm combining time and accuracy was used to grade performance. Voluntary postperformance surveys were used to evaluate the experience. RESULTS: Results demonstrate that more experienced residents have statistically significant better scores and completed the procedure in less time than inexperienced residents. Survey results revealed that most residents agreed that practice on the simulator would help with future ventriculostomies. CONCLUSION: This mixed reality simulator provides a real-life experience, and will be an instrumental tool in training the next generation of neurosurgeons. We have now implemented a standard where incoming residents must prove efficiency and skill on the simulator before their first interaction with a patient. ABBREVIATIONS: AANS, American Association of Neurological Surgeons EVD, external ventricular drain PGY, postgraduate year SNS, Society Neurological Surgeons

Long-term growth and alignment after occipitocervical and atlantoaxial fusion with rigid internal fixation in young children

OBJECT The long-term consequences of atlantoaxial (AA) and occipitocervical (OC) fusion and instrumentation in young children are unknown. Anecdotal reports have raised concerns regarding altered growth and alignment of the cervical spine after surgical intervention. The purpose of this study was to determine the long-term effects of these surgeries on the growth and alignment of the maturing spine. METHODS A multiinstitutional retrospective chart review was conducted for patients less than or equal to 6 years of age who underwent OC or AA fusion with rigid instrumentation at 9 participating centers. All patients had at least 3 years of clinical and radiographic follow-up data and radiographically confirmed fusion. Preoperative, immediate postoperative, and most recent follow-up radiographs and/or CT scans were evaluated to assess changes in spinal growth and alignment. RESULTS Forty children (9 who underwent AA fusion and 31 who underwent OC fusion) were included in the study (mean follow-up duration 56 months). The mean vertical growth over the fused levels in the AA fusion patients represented 30% of the growth of the cervical spine (range 10%-50%). Three different vertical growth patterns of the fusion construct developed among the 31 OC fusion patients during the follow-up period: 1) 16 patients had substantial growth (13%-46% of the total growth of the cervical spine); 2) 9 patients had no meaningful growth; and 3) 6 patients, most of whom presented with a distracted atlantooccipital dislocation, had a decrease in the height of the fused levels (range 7-23 mm). Regarding spinal alignment, 85% (34/40) of the patients had good alignment at follow-up, with straight or mildly lordotic cervical curvatures. In 1 AA fusion patient (11%) and 5 OC fusion patients (16%), we observed new hyperlordosis (range 43°-62°). There were no cases of new kyphosis or swan-neck deformity, evidence of subaxial instability, or unintended subaxial fusion. No preoperative predictors of these growth patterns or alignment were evident. CONCLUSIONS These results demonstrate that most young children undergoing AA and OC fusion with rigid internal fixation continue to have good cervical alignment and continued growth within the fused levels during a prolonged follow-up period. However, some variability in vertical growth and alignment exists, highlighting the need to continue close long-term follow-up.

Helmet use and cervical spine injury: a review of motorcycle, moped, and bicycle accidents at a level 1 trauma center.

Helmet use in two-wheeled vehicle accidents is widely reported to decrease the rates of death and traumatic brain injury. Previous reports suggest that there exists a trade off with helmet use consisting of an increased risk of cervical spine injuries. Recently, a review of a national trauma database demonstrated the opposite, with reduction in cervical spinal cord injuries in motorcycle crashes (MCC). In 2000, the State of Florida repealed its mandatory helmet law to make helmet use optional for individuals older than 21 with

Insurance status influences the rates of reportable quality metrics in brain tumor patients: a nationwide inpatient sample study.

10,000 of health insurance coverage. To better ascertain the risks of cervical spine injury with non-helmet use in all two-wheeled vehicles, we analyzed the University of Florida level one trauma center experience. We reviewed the Traumatic injury database over a five-year period (January 1, 2005, to July 1, 2010) for all patients involved in two-wheeled vehicle accidents. Patients were stratified according to vehicle type (motorcycle, scooter, and bicycle), helmet use, and the presence or absence of a cervical spine injury. Outcomes were compared for injury severity, cervical spine injury, cervical spinal cord injury, and presence of cervical spine injuries requiring surgery. Population means were compared using paired t-test. A total of 1331 patients were identified: 995 involved in motorcycle accidents, 87 involved in low-powered scooter accidents, and 249 involved in bicycle accidents. Helmet use was variable between each group. One hundred thirty-five total cervical spine injuries were identified. No evidence was found to suggest an increased risk of cervical spine injury or increased severity of cervical spine injury with helmet use. This fact, in combination with our previous findings, suggest that the laws age and insurance exemption should be revoked and a universal helmet law be reinstated in the state of Florida.

Characterization of Gene Expression Phenotype in Amyotrophic Lateral Sclerosis Monocytes.

BACKGROUND In 2010, the Patient Protection and Affordable Care Act was passed to expand health insurance, narrow health care disparities, and improve health care quality in the United States. As part of this initiative, the Agency for Healthcare Research and Quality and the Centers for Medicare and Medicaid Services are now tracking quality metrics. OBJECTIVE To analyze the effects of insurance on the incidence of patient safety indicators (PSIs) and hospital-acquired conditions (HACs) using the Nationwide Inpatient Sample for patients who have brain tumors. METHODS The Nationwide Inpatient Sample was queried for all hospitalizations between 2002 and 2011 involving patients with brain tumors. Because of the confounding age restriction with Medicare, comparisons were made between Medicaid/self-pay and private insurance. To determine which factors contributed to HACs and PSIs, odds ratios were calculated for each risk factor. Logistic regression models were used to assess the effect of payer status on individual PSIs, HACs, and patient outcomes. RESULTS Medicaid/self-pay patients had a higher PSI and HAC incidence compared with private insurance patients. The greater incidence of PSIs and HACs correlated with increased length of stay, worse discharge outcomes, and increased in-hospital mortality. CONCLUSION Variability exists in the incidence of PSIs and HACs in patients with brain tumors based on insurance status. Controlling for both patient and hospital factors can explain these differences. The cause of these disparities should be studied prospectively to begin the process of improving quality metrics in vulnerable patient populations.

Ogilvie's syndrome after pediatric spinal deformity surgery: successful treatment with neostigmine

Importance Amyotrophic lateral sclerosis (ALS) is a common adult-onset neurodegenerative disease characterized by selective loss of upper and lower motor neurons. Patients with ALS have persistent peripheral and central inflammatory responses including abnormally functioning T cells and activated microglia. However, much less is known about the inflammatory gene profile of circulating innate immune monocytes in these patients. Objective To characterize the transcriptomics of peripheral monocytes in patients with ALS. Design, Setting, and Participants Monocytes were isolated from peripheral blood of 43 patients with ALS and 22 healthy control individuals. Total RNA was extracted from the monocytes and subjected to deep RNA sequencing, and these results were validated by quantitative reverse transcription polymerase chain reaction. Main Outcomes and Measures The differential expressed gene signatures of these monocytes were identified using unbiased RNA sequencing strategy for gene expression profiling. Results The demographics between the patients with ALS (mean [SD] age, 58.8 [1.57] years; 55.8% were men and 44.2% were women; 90.7% were white, 4.65% were Hispanic, 2.33% were black, and 2.33% were Asian) and control individuals were similar (mean [SD] age, 57.6 [2.15] years; 50.0% were men and 50.0% were women; 90.9% were white, none were Hispanic, none were black, and 9.09% were Asian). RNA sequencing data from negative selected monocytes revealed 233 differential expressed genes in ALS monocytes compared with healthy control monocytes. Notably, ALS monocytes demonstrated a unique inflammation-related gene expression profile, the most prominent of which, including IL1B, IL8, FOSB, CXCL1, and CXCL2, were confirmed by quantitative reverse transcription polymerase chain reaction (IL8, mean [SE], 1.00 [0.18]; P = .002; FOSB, 1.00 [0.21]; P = .009; CXCL1, 1.00 [0.14]; P = .002; and CXCL2, 1.00 [0.11]; P = .01). Amyotrophic lateral sclerosis monocytes from rapidly progressing patients had more proinflammatory DEGs than monocytes from slowly progressing patients. Conclusions and Relevance Our data indicate that ALS monocytes are skewed toward a proinflammatory state in the peripheral circulation and may play a role in ALS disease progression, especially in rapidly progressing patients. This increased inflammatory response of peripheral immune cells may provide a potential target for disease-modifying therapy in patients with ALS.

External ventricular drain practice variations: results from a nationwide survey

Ogilvies syndrome is a rare and potentially fatal disease that can easily be mistaken for postoperative ileus. Also known as acute colonic pseudo-obstruction, early recognition and diagnosis of the syndrome allows for treatment prior to bowel perforation and requisite abdominal surgery. The authors report a case of Ogilvies syndrome following spinal deformity correction and tethered cord release in an adolescent who presented with acute abdominal distension, nausea, and vomiting on postoperative Day 0. The patient was initially diagnosed with adynamic ileus and treated conservatively with bowel rest, reduction in narcotic dosage, and a regimen of stool softeners, laxatives, and enemas. Despite this treatment, her clinical course failed to improve, and she demonstrated significant colonic distension radiographically. Intravenous neostigmine was administered as a bolus with a rapid and dramatic response. This case is the first reported instance of neostigmine use for Ogilvies syndrome treatment following a pediatric neurosurgical operation.