Phosphorylation of aryl hydrocarbon receptor interacting protein by TBK1 negatively regulates IRF7 and the type I interferon response.

The innate antiviral response to RNA viruses is initiated by sensing of viral RNAs by RIG-I-like receptors and elicits type I interferon (IFN) production, which stimulates the expression of IFN-stimulated genes that orchestrate the antiviral response to prevent systemic infection. Negative regulation of type I IFN and its master regulator, transcription factor IRF7, is essential to maintain immune homeostasis. We previously demonstrated that AIP (aryl hydrocarbon receptor interacting protein) functions as a negative regulator of the innate antiviral immune response by binding to and sequestering IRF7 in the cytoplasm, thereby preventing IRF7 transcriptional activation and type I IFN production. However, it remains unknown how AIP inhibition of IRF7 is regulated. We show here that the kinase TBK1 phosphorylates AIP and Thr40 serves as the primary target for TBK1 phosphorylation. AIP Thr40 plays critical roles in regulating AIP stability and mediating its interaction with IRF7. The AIP phosphomimetic T40E exhibited increased proteasomal degradation and enhanced interaction with IRF7 compared with wildtype AIP. AIP T40E also blocked IRF7 nuclear translocation, which resulted in reduced type I IFN production and increased viral replication. In sharp contrast, AIP phosphonull mutant T40A had impaired IRF7 binding, and stable expression of AIP T40A in AIP-deficient mouse embryonic fibroblasts elicited a heightened type I IFN response and diminished RNA virus replication. Taken together, these results demonstrate that TBK1-mediated phosphorylation of AIP at Thr40 functions as a molecular switch that enables AIP to interact with and inhibit IRF7, thus preventing overactivation of type I IFN genes by IRF7.

Viscoelastic Testing and Coagulopathy of Traumatic Brain Injury.

A unique coagulopathy often manifests following traumatic brain injury, leading the clinician down a difficult decision path on appropriate prophylaxis and therapy. Conventional coagulation assays-such as prothrombin time, partial thromboplastin time, and international normalized ratio-have historically been utilized to assess hemostasis and guide treatment following traumatic brain injury. However, these plasma-based assays alone often lack the sensitivity to diagnose and adequately treat coagulopathy associated with traumatic brain injury. Here, we review the whole blood coagulation assays termed viscoelastic tests and their use in traumatic brain injury. Modified viscoelastic tests with platelet function assays have helped elucidate the underlying pathophysiology and guide clinical decisions in a goal-directed fashion. Platelet dysfunction appears to underlie most coagulopathies in this patient population, particularly at the adenosine diphosphate and/or arachidonic acid receptors. Future research will focus not only on the utility of viscoelastic tests in diagnosing coagulopathy in traumatic brain injury, but also on better defining the use of these tests as evidence-based and/or precision-based tools to improve patient outcomes.

Thromboelastography-Guided Therapy of Hemorrhagic Complications after Craniopharyngioma Resection: Case-Based Update.

PURPOSE: Thromboelastography (TEG) is a point-of-care test that evaluates the entire hemostatic process. The use of TEG is expanding in multiple pediatric surgical disciplines. However, there is very little literature regarding its application in pediatric neurosurgical patients. METHODS: The authors provide a case-based update and literature review regarding potential applications of TEG to pediatric neurosurgical patients. RESULTS: The authors describe a 12-year-old female who experienced a number of complications after a craniopharyngioma resection. The patient suffered multiple new intraventricular hemorrhages with removal of external ventricular drains. Standard coagulopathy tests did not reveal any abnormalities. However, an abnormal TEG value suggested primary hyperfibrinolysis, which led to a change in medical management. The patient did not suffer any further bleeding episodes after the change in treatment. CONCLUSIONS: The authors discuss a case where TEG influenced patient management and identified a problem despite normal values of standard laboratory tests. Neurosurgeons should be aware of the potential benefits for TEG testing in pediatric patients.

Predictors of Outcomes and Complications After Microsurgical and Endovascular Treatment of 1300 Intracranial Aneurysms.

BACKGROUND: We performed a rigorous statistical analysis of the complications and outcomes of patients with ruptured or unruptured intracranial aneurysms. Our emphasis was on the potential predictive factors when both surgical and endovascular management are offered by a team with balanced microsurgical and endovascular expertise. METHODS: From January 2005 to December 2011, 1297 consecutive patients presenting with ruptured (n=829) or unruptured (n=468) aneurysms were prospectively enrolled in our vascular database. The treatment modality was determined by consensus of the endovascular and microsurgical teams. The patients' medical and neurological conditions and aneurysm characteristics were compared against the postintervention complication rates and outcomes using multivariate analyses. RESULTS: The patients mostly underwent clipping for ruptured (63.7%) or unruptured (56.6%) aneurysms. For ruptured aneurysms, higher Hunt and Hess and Fisher grades on admission were key predictors of increased neurological (P < 0.001 and P < 0.001, respectively) and medical (P < 0.001 and P=0.041, respectively) complication rates. No significant differences in the outcomes were observed between the coiling or clipping groups during the follow-up period. For the unruptured group, a family history of intracranial aneurysms was the most relevant predictor for reducing neurological complication rates and increasing survival at 6 months. Hypertension was, however, the strongest factor associated with complications negatively affecting the outcomes. CONCLUSIONS: For the ruptured and unruptured groups both, the outcomes were generally good, although neurological and medical complications were reasonably more frequent for the ruptured aneurysms. Coiling provided a sustained benefit in lowering the complication rates only in the short term for the unruptured aneurysms. Smoking was associated, paradoxically, with improved outcomes.

Risk of deep venous thrombosis in elective neurosurgical procedures: a prospective, Doppler ultrasound-based study in children 12 years of age or younger.

OBJECTIVE The risk of venous thromboembolism (VTE) from deep venous thrombosis (DVT) is significant in neurosurgical patients. VTE is considered a leading cause of preventable hospital deaths and preventing DVT is a closely monitored quality metric, often tied to accreditation, hospital ratings, and reimbursement. Adult protocols include prophylaxis with anticoagulant medications. Children's hospitals may adopt adult protocols, although the incidence of DVT and the risk or efficacy of treatment is not well defined. The incidence of DVT in children is likely less than in adults, although there is very little prospectively collected information. Most consider the risk of DVT to be extremely low in children 12 years of age or younger. However, this consideration is based on tradition and retrospective reviews of trauma databases. In this study, the authors prospectively evaluated pediatric patients undergoing a variety of elective neurosurgical procedures and performed Doppler ultrasound studies before and after surgery. METHODS A total of 100 patients were prospectively enrolled in this study. All of the patients were between the ages of 1 month and 12 years and were undergoing elective neurosurgical procedures. The 91 patients who completed the protocol received a bilateral lower-extremity Doppler ultrasound examination within 48 hours prior to surgery. Patients did not receive either medical or mechanical DVT prophylaxis during or after surgery. The ultrasound examination was repeated within 72 hours after surgery. An independent, board-certified radiologist evaluated all sonograms. We prospectively collected data, including potential risk factors, details of surgery, and details of the clinical course. All patients were followed clinically for at least 1 year. RESULTS There was no clinical or ultrasound evidence of DVT or VTE in any of the 91 patients. There was no clinical evidence of VTE in the 9 patients who did not complete the protocol. CONCLUSIONS In this prospective study, no DVTs were found in 91 patients evaluated by ultrasound and 9 patients followed clinically. While the study is underpowered to give a definitive incidence, the data suggest that the risk of DVT and VTE is very low in children undergoing elective neurosurgical procedures. Prophylactic protocols designed for adults may not apply to pediatric patients. Clinical trial registration no.: NCT02037607 (clinicaltrials.gov).

Transfer of children with isolated linear skull fractures: is it worth the cost?

OBJECTIVE Children with skull fractures are often transferred to hospitals with pediatric neurosurgical capabilities. Historical data suggest that a small percentage of patients with an isolated skull fracture will clinically decline. However, recent papers have suggested that the risk of decline in certain patients is low. There are few data regarding the financial costs associated with transporting patients at low risk for requiring specialty care. In this study, the clinical outcomes and financial costs of transferring of a population of children with isolated skull fractures to a Level 1 pediatric trauma center over a 9-year period were analyzed. METHODS A retrospective review of all children treated for head injury at Riley Hospital for Children (Indianapolis, Indiana) between 2005 and 2013 was performed. Patients with a skull fracture were identified based on ICD-9 codes. Patients with intracranial hematoma, brain parenchymal injury, or multisystem trauma were excluded. Children transferred to Riley Hospital from an outside facility were identified. The clinical and radiographic outcomes were recorded. A cost analysis was performed on patients who were transferred with an isolated, linear, nondisplaced skull fracture. RESULTS Between 2005 and 2013, a total of 619 pediatric patients with isolated skull fractures were transferred. Of these, 438 (70.8%) patients had a linear, nondisplaced skull fracture. Of these 438 patients, 399 (91.1%) were transferred by ambulance and 39 (8.9%) by helicopter. Based on the current ambulance and helicopter fees, a total of $1,834,727 (an average of $4188.90 per patient) was spent on transfer fees alone. No patient required neurosurgical intervention. All patients recovered with symptomatic treatment; no patient suffered late decline or epilepsy. CONCLUSIONS This study found that nearly $2 million was spent solely on transfer fees for 438 pediatric patients with isolated linear skull fractures over a 9-year period. All patients in this study had good clinical outcomes, and none required neurosurgical intervention. Based on these findings, the authors suggest that, in the absence of abuse, most children with isolated, linear, nondisplaced skull fractures do not require transfer to a Level 1 pediatric trauma center. The authors suggest ideas for further study to refine the protocols for determining which patients require transport.

Current Guidelines on Syncope.

Syncope is a very commonly encountered clinical problem in general practice and in the emergency department. In the evaluation of syncope, it is important to identify the specific cause to determine the treatment, to estimate the precise risk to a patient, and to reduce recurrence. Sometimes, making a diagnosis of syncope is difficult, as different mechanisms may often coexist. Syncope causes a significant impact on quality of life due to associated risk of physical injury. In particular, syncope can be a precursor to sudden cardiac death in patients with underlying cardiac disease. It is crucial to identify patients at increased risk of death, such as those with myocardial ischemia and/or potentially life-threatening genetic diseases (e.g., Long-QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and arrhythmogenic right ventricular dysplasia). After these conditions have been excluded, other benign conditions that cause syncope must be identified, and efforts should be made to improve quality of life. The lack of a gold-standard clinical tool to aid in diagnosing syncope as well as improper use of various diagnostic tests, are leading to high economic burdens in this area.

Intracranial chordoma presenting as acute hemorrhage in a child: Case report and literature review.

BACKGROUND: Chordomas are rare, slow-growing malignant neoplasms derived from remnants of the embryological notochord. Pediatric cases comprise only 5% of all chordomas, but more than half of the reported pediatric chordomas are intracranial. For patients of all ages, intracranial chordomas typically present with symptoms such as headaches and progressive neurological deficits occurring over several weeks to many years as they compress or invade local structures. There are only reports of these tumors presenting acutely with intracranial hemorrhage in adult patients. CASE DESCRIPTION: A 10-year-old boy presented with acute onset of headache, emesis, and diplopia. Head computed tomography and magnetic resonance imaging of brain were suspicious for a hemorrhagic mass located in the left petroclival region, compressing the ventral pons. The mass was surgically resected and demonstrated acute intratumoral hemorrhage. Pathologic examination was consistent with chordoma. CONCLUSION: There are few previous reports of petroclival chordomas causing acute intracranial hemorrhage. To the authors' knowledge, this is the first case of a petroclival chordoma presenting as acute intracranial hemorrhage in a pediatric patient. Although uncommon, it is important to consider chordoma when evaluating a patient of any age presenting with a hemorrhagic lesion of the clivus.

Analysis of the potential risk of central intravenous lines and/or total parenteral nutrition with ventriculoatrial shunts.

OBJECT: The distal catheter of a ventriculoatrial (VA) cerebrospinal fluid shunt is potentially exposed to bacterial seeding from a subclavian central line. The risk of blood stream infections (BSIs) from central lines increases with administration of total parenteral nutrition (TPN). The potential risks of shunt malfunction or infection in patients with a VA shunt and a concurrent subclavian central line and/or TPN administration have not been studied. METHODS: A retrospective review of 49 pediatric patients with placement of a VA shunt was performed. Three outcome measures were studied: shunt malfunction, shunt infection, and bacteremia/fungemia requiring shunt removal. All outcomes were measured by 1 year after shunt insertion. We analyzed the following potential risk factors: age at shunt insertion, prior ventriculoperitoneal (VP) shunt, prior shunt infection, abdominal infection/necrotizing enterocolitis (NEC), concurrent subclavian central line, and administration of TPN. The association between each risk factor and outcome was evaluated using Fisher's exact test to generate the relative risk. Additionally, a logistic regression analysis was performed to evaluate the odds ratio of the outcomes to risk factors considering age as a covariate. RESULTS: The average age at shunt insertion was 6.3 ± 7.6 years. The most common diagnosis was posthemorrhagic hydrocephalus of prematurity (53.1 %). Fifteen patients (30.1 %) had a shunt malfunction within 1 year, 6 (12.2 %) had a shunt infection, and 3 (6.1 %) required removal of the shunt due to bacteremia/fungemia. The age at shunt insertion was not a statistically significant independent risk factor for any of the three outcomes. Prior shunt infection predicted an increased risk for both future shunt malfunction and infection in both the associative relative risk analysis and the age-dependent logistic regression analysis, although the correlation did not reach statistical significance. The presence of a subclavian central line or TPN administration did not statistically increase the risk over baseline for any of the outcomes in either analysis. CONCLUSIONS: The relatively small number of patients limits the power of the study. Considering this limitation, the data suggests that the presence of a concurrent subclavian central line or administration of TPN does not increase the risk of shunt malfunction or infection over the baseline of this high-risk cohort.

Risk of radiation-induced malignancies from CT scanning in children who underwent shunt treatment before 6 years of age: a retrospective cohort study with a minimum 10-year follow-up.

OBJECT: A number of mathematical models predict the risk of future cancer from the ionizing radiation exposure of CT scanning. The predictions are alarming. Some models predict 29,000 future cancers and 14,500 deaths in the US will be directly caused by 1 year's worth of CT scanning. However, there are very few clinical data to justify or refute these claims. Young children are theoretically highly susceptible to the damaging effects of radiation. In this study, the authors examined children who underwent CSF shunt placement before 6 years of age. The authors chose to study shunt-treated patients with the assumption that these patients would undergo future imaging, facilitating surveillance. They chose a study period of 1991-2001 to allow more than 10 years of follow-up data. METHODS: The authors studied 104 consecutive children who underwent CSF shunt placement prior to 6 years of age and who had at least 10 years of follow-up data. Sixty-two of these patients underwent shunt placement prior to 1 year of age. The age at the initial scanning session, the number of future CT scanning sessions, diagnosis, and results of any future studies were recorded. The age-specific radiation dose was calculated for children younger than 1 year. Children younger than 1 year at the time of shunt placement were evaluated separately, based on the assumption that they represented the highest risk cohort. The authors examined all data for any evidence of future leukemia or head/neck tumor (benign or malignant). RESULTS: These children underwent a total of 1584 CT scanning sessions over a follow-up period of 1622 person-years. A total of 517 scanning sessions were performed prior to 6 years of age, including 260 in the 1st year of life. Children who underwent shunt placement before 1 year of age underwent an average of 16.3 ± 13.5 CT sessions (range 1-41). Children undergoing placement between 1 and 6 years of age received an average of 14.1 ± 12.5 CT studies (range 5-52). There were no subsequent tumors (benign or malignant) or leukemia detected. CONCLUSIONS: Previously published models predict a significant number of future cancers directly caused by CT scanning. However, there are very few published clinical data. In the authors' study, zero future radiation-induced malignancies were detected after routine CT scanning in a high-risk group. While the authors do not consider their single-institution study adequate to define the actual risk, their data suggest that the overall risk is low. The authors hope this study encourages future collaborative efforts to define the actual risk to patients.

Outcomes of spinal fusion following autologous stem cell transplantation.

Patients who have undergone myeloablative chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) for conditions such as multiple myeloma, Hodgkin's disease, and primary amyloidosis may be at higher risk for failure of spinal fusion. As HSCT care and outcomes continue to improve, it is increasingly likely that neurosurgeons will encounter patients post-HSCT who require spinal procedures. To our knowledge there are no published data on fusion outcomes in this unique patient population. We report three patients who underwent spinal fusion following an autologous HSCT. Spinal surgery was performed, on average, 4.5 years after autologous HSCT. No patients were on immunosuppressant chemotherapy at the time of the procedure, although one patient was being treated with rituximab for disease progression peri-operatively. Average radiographic confirmation of fusion was 37 months and all patients ultimately demonstrated fusion, although not without incident. Our results suggest that spinal fusion can occur in patients who have previously undergone myeloablative chemotherapy followed by autologous HSCT.

Computed-tomography-based anatomical study to assess feasibility of pedicle screw placement in the lumbar and lower thoracic pediatric spine.

PURPOSE: The anatomy of the pedicle is complex and three-dimensional; however, there are basic dimensions important for possible screw placement. There are relatively few studies examining the pedicle anatomy in children. This study was performed to evaluate the feasibility of pedicle screw placement in children aged 5-16, based on key anatomic dimensions. A case illustration is also provided. METHODS: The CT scans of 102 consecutive children were studied. Patients with abnormal anatomy were excluded. The parameters of the pedicle isthmus width (W), estimation of screw length (L), and axial angle (A) were recorded for 1,632 pedicles from T10 through L5. Patients were divided into four age groups. Statistical analysis was performed evaluating the difference between males and females and of the particular anatomy at the thoracolumbar junction. RESULTS: The pedicles increase in both L and W from T10-T12 and from L1-L5. L1 has a consistently smaller W compared to T12 in both genders over all age ranges. Estimating a W of 4.5 mm necessary for safe screw placement, we calculate that virtually all pedicles of T12 and L3-L5 are large enough for screw placement in both genders after age 8. L4 and L5 are large enough for screw placement in both genders in the youngest age range. CONCLUSIONS: Most of the pedicles of the lower lumbar spine and T12 are large enough to house the smallest commercially available screw. Understanding of the anatomy at the thoracolumbar junction is important, as the W of L1 is consistently smaller than T12.

Spinal surgery following organ transplantation.

OBJECT: Organ transplantation for renal, liver, cardiac, and pulmonary failure has become more common in recent years, and patients are living longer as a result of improved organ preservation methods, immunosuppressive regimens, and general posttransplant care. Some of these patients undergo spine fusion surgery following organ transplantation, and there is little available information concerning outcomes. The authors report on their experience with and the outcomes of spine fusion in this rare and unique immunosuppressed patient group. METHODS: Using the Current Procedural Terminology and ICD-9 codes for solid organ transplants, bone marrow transplantations (BMTs), and spine fusion surgeries, the authors searched their patient database between 1997 and 2008. Data points of interest included primary diagnosis, type of organ transplant, immunosuppressant drug therapy, complications from spine surgery, and radiographic analysis of spine fusion. Spine fusion was assessed with CT or radiography at the latest follow-up. RESULTS: The database search results revealed 5999 patients who underwent heart, lung, liver, kidney, pancreas, intestine, or bone marrow transplant between 1997 and 2008. Eighteen of the 5999 patients underwent a spine fusion surgery while receiving immunosuppressive therapy. Organ transplants included kidney, liver, heart, pancreas, and allogenic BMT. There were 3 deaths unrelated to spine fusion within 1 year of the surgery and 1 death immediately after spine surgery. Graft-versus-host disease developed in 1 patient when prednisone was stopped prior to the spine surgery. Thirteen patients underwent follow-up radiographic imaging at an average of 25 months after spine surgery; 12 demonstrated radiographic fusion. CONCLUSIONS: The results suggest that spine fusion rates are adequate despite immunosuppressive therapy in patients undergoing spinal fusion after transplant procedures. The data also illustrate the high morbidity and mortality rates found in the organ transplant patient population.