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Jian Guan, Jay Riva-Cambrin and Douglas L. Brockmeyer

OBJECTIVE

Patients treated for Chiari I malformation (CM-I) with posterior fossa decompression (PFD) may occasionally and unpredictably develop postoperative hydrocephalus. The clinical risk factors predictive of this type of Chiari-related hydrocephalus (CRH) are unknown. The authors' objective was to evaluate their experience to identify risk factors that may predict which of these patients undergoing PFD will develop CRH after surgery.

METHODS

The authors performed a retrospective clinical chart review of all patients who underwent PFD surgery and duraplasty for CM-I at the Primary Children's Hospital in Utah from June 1, 2005, through May 31, 2015. Patients were dichotomized based on the need for long-term CSF diversion after PFD. Analysis included both univariate and multivariable logistic regression analyses.

RESULTS

The authors identified 297 decompressive surgeries over the period of the study, 22 of which required long-term postoperative CSF diversion. On multivariable analysis, age < 6 years old (OR 3.342, 95% CI 1.282–8.713), higher intraoperative blood loss (OR 1.003, 95% CI 1.001–1.006), and the presence of a fourth ventricular web (OR 3.752, 95% CI 1.306–10.783) were significantly associated with the need for long-term CSF diversion after decompressive surgery.

CONCLUSIONS

Younger patients, those with extensive intraoperative blood loss, and those found during surgery to have a fourth ventricular web were at higher risk for the development of CRH. Clinicians should be alert to evidence of CRH in this patient population after PFD surgery.

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Spencer Twitchell, Michael Karsy, Jian Guan, William T. Couldwell and Philipp Taussky

The term “radiation vasculopathy” defines a heterogeneous and poorly defined complex of vessel injury due to radiation. Radiation vasculopathy remains underrecognized and poorly treated with respect to head and neck radiotherapy. Distinct injury patterns to small (≤ 100-μm), medium (> 100-μm), and large (> 500-μm) vessels can occur, resulting in carotid stenosis, intracranial stenosis, and vascular anomalies (e.g., cavernous malformations, aneurysms). Because of the lack of clinical evidence and guidelines, treatment plans involve medical management, carotid endarterectomy, and carotid artery stenting and are developed on a patient-by-patient basis. In this review, the authors discuss the current pathophysiology, imaging, clinical impact, and potential treatment strategies of radiation vasculopathy with clinical pertinence to practicing neurosurgeons and neurologists. A review of 4 patients with prior head and neck tumors in whom delayed radiation vasculopathy developed after radiotherapy demonstrates the application of various treatment options in a case-by-case manner. Earlier recognition of radiation vasculopathy disease patterns may enable earlier initiation of treatment and monitoring for complications. Standardized terminology and treatments may assist with improving clinical outcomes.

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Michael Karsy, Jian Guan and L. Eric Huang

OBJECTIVE

Gliomas are one of the most common types of primary brain tumors. Recent studies have supported the importance of key genetic alterations, including isocitrate dehydrogenase (IDH) mutations and 1p19q codeletion, in glioma prognosis. Mutant IDH produces 2-hydroxyglutarate from α-ketoglutarate, a key metabolite of the Krebs cycle. The mitochondrial pyruvate carrier (MPC) is composed of MPC1 and MPC2 subunits and is functionally essential for the Krebs cycle. The authors sought to explore the impact of MPC1 and MPC2 expression on patient prognosis.

METHODS

Genomic and clinical data in patients with lower-grade glioma (WHO grades II and III) from The Cancer Genome Atlas (TCGA) were evaluated using Kaplan-Meier analysis and hazards modeling. Validation was conducted with additional data sets, including glioblastoma.

RESULTS

A total of 286 patients with lower-grade glioma (mean age 42.7 ± 13.5 years, 55.6% males) included 54 cases of IDH–wild type (18.9%); 140 cases of IDH-mutant, 1p19q-intact (49.0%); and 85 cases of IDH-mutant, 1p19q-codeleted (29.7%) tumors. Kaplan-Meier analysis showed that an MPC1 z-score > 0 distinguished better survival, particularly in IDH-mutant (p < 0.01) but not IDH–wild type tumors. Conversely, an MPC2 z-score > 0 identified worsened survival, particularly in IDH-mutant (p < 0.01) but not IDH–wild type tumors. Consistently, neither MPC1 nor MPC2 was predictive in a glioblastoma data set containing 5% IDH-mutant cases. Within the IDH-stratified lower-grade glioma data set, MPC1 status distinguished improved survival in 1p19q-codeleted tumors (p < 0.05), whereas MPC2 expression delineated worsened survival in 1p19q-intact tumors (p < 0.01). A hazards model identified IDH and 1p19q status, age (p = 0.01, HR = 1.03), Karnofsky Performance Scale (KPS) score (p = 0.03, HR = 0.97), and MPC1 (p = 0.003, HR = 0.52) but not MPC2 (p = 0.38) as key variables affecting overall survival. Further validation confirmed MPC1 as an independent predictor of lower-grade glioma. A clinical risk score using IDH and 1p19q status, age, KPS score, and MPC1 and MPC2 z-scores defined 4 risk categories for lower-grade glioma; this score was validated using a secondary glioma data set.

CONCLUSIONS

These results support the importance of MPC, especially MPC1, in improving prognostication of IDH-mutant tumors. The generation of a risk score system directly translates this finding to clinical application; however, further research to improve the molecular understanding of the role of MPC in the metabologenomic regulation of gliomas is warranted.

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Michael Karsy, Andrea Brock, Jian Guan, Phillip Taussky, M. Yashar S. Kalani and Min S. Park

Stroke is a leading cause of disability in the US. Although there has been significant progress in the area of medical and surgical thrombolytic technologies, neuroprotective agents to prevent secondary cerebral injury and to minimize disability remain limited. Only limited success has been reported in preclinical and clinical trials evaluating a variety of compounds. In this review, the authors discuss the most up-to-date information regarding the underlying molecular biology of stroke as well as strategies that aim to mitigate this complex signaling cascade. Results of historical research trials involving N-methyl-d-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonists, clomethiazole, antioxidants, citicoline, nitric oxide, and immune regulators have laid the groundwork for current progress. In addition, more recent studies involving therapeutic hypothermia, magnesium, albumin, glyburide, uric acid, and a variety of other treatments have provided more options. The use of neuroprotective agents in combination or with existing thrombolytic treatments may be one of many exciting areas of further development. Although past trials of neuroprotective agents in ischemic stroke have been limited, significant insights into mechanisms of stroke, animal models, and trial design have incrementally improved approaches for future therapies.

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Jian Guan, Chad D. Cole, Meic H. Schmidt and Andrew T. Dailey

OBJECTIVE

Blood loss during surgery for thoracolumbar scoliosis often requires blood product transfusion. Rotational thromboelastometry (ROTEM) has enabled the more targeted treatment of coagulopathy, but its use in deformity surgery has received limited study. The authors investigated whether the use of ROTEM reduces transfusion requirements in this case-control study of thoracolumbar deformity surgery.

METHODS

Data were prospectively collected on all patients who received ROTEM-guided blood product management during long-segment (≥ 7 levels) posterior thoracolumbar fusion procedures at a single institution from April 2015 to February 2016. Patients were matched with a group of historical controls who did not receive ROTEM-guided therapy according to age, fusion segments, number of osteotomies, and number of interbody fusion levels. Demographic, intraoperative, and postoperative transfusion requirements were collected on all patients. Univariate analysis of ROTEM status and multiple linear regression analysis of the factors associated with total in-hospital transfusion volume were performed, with p < 0.05 considered to indicate statistical significance.

RESULTS

Fifteen patients who received ROTEM-guided therapy were identified and matched with 15 non-ROTEM controls. The mean number of fusion levels was 11 among all patients, with no significant differences between groups in terms of fusion levels, osteotomy levels, interbody fusion levels, or other demographic factors. Patients in the non-ROTEM group required significantly more total blood products during their hospitalization than patients in the ROTEM group (8.5 ± 4.2 units vs 3.71 ± 2.8 units; p = 0.001). Multiple linear regression analysis showed that the use of ROTEM (p = 0.016) and a lower number of fused levels (p = 0.022) were associated with lower in-hospital transfusion volumes.

CONCLUSIONS

ROTEM use during thoracolumbar deformity correction is associated with lower transfusion requirements. Further investigation will better define the role of ROTEM in transfusion during deformity surgery.

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Spencer Twitchell, Michael Karsy, Jared Reese, Jian Guan, William T. Couldwell, Andrew Dailey and Erica F. Bisson

OBJECTIVE

Efforts to examine the value of care—combining both costs and quality—are gaining importance in the current health care climate. This thrust is particularly evident in treating common spinal disease where both incidences and costs are generally high and practice patterns are variable. It is often challenging to obtain direct surgical costs for these analyses, which hinders the understanding of cost drivers and cost variation. Using a novel tool, the authors sought to understand the costs of posterior lumbar arthrodesis with interbody devices.

METHODS

The Value Driven Outcomes (VDO) database at the University of Utah was used to evaluate the care of patients who underwent open or minimally invasive surgery (MIS), 1- and 2-level lumbar spine fusion (Current Procedural Terminology code 22263). Patients treated from January 2012 through June 2017 were included.

RESULTS

A total of 276 patients (mean age 58.9 ± 12.4 years) were identified; 46.7% of patients were men. Most patients (82.2%) underwent 1-level fusion. Thirteen patients (4.7%) had major complications and 11 (4.1%) had minor complications. MIS (β = 0.16, p = 0.002), length of stay (β = 0.47, p = 0.0001), and number of operated levels (β = 0.37, p = 0.0001) predicted costs in a multivariable analysis. Supplies and implants (55%) and facility cost (36%) accounted for most of the expenditure. Other costs included pharmacy (7%), laboratory (1%), and imaging (1%).

CONCLUSIONS

These results provide direct cost accounting for lumbar fusion procedures using the VDO database. Efforts to improve the value of lumbar surgery should focus on high cost areas, i.e., facility and supplies/implant.

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Michael Karsy, Jayson A. Neil, Jian Guan, Mark A. Mahan, Howard Colman and Randy L. Jensen

Despite extensive efforts in research and therapeutics, achieving longer survival for patients with glioblastoma (GBM) remains a formidable challenge. Furthermore, because of rapid advances in the scientific understanding of GBM, communication with patients regarding the explanations and implications of genetic and molecular markers can be difficult. Understanding the important biomarkers that play a role in GBM pathogenesis may also help clinicians in educating patients about prognosis, potential clinical trials, and monitoring response to treatments. This article aims to provide an up-to-date review that can be discussed with patients regarding common molecular markers, namely O-6-methylgua-nine-DNA methyltransferase (MGMT), isocitrate dehydrogenase 1 and 2 (IDH1/2), p53, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), Phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and 1p/19q. The importance of the distinction between a prognostic and a predictive biomarker as well as clinical trials regarding these markers and their relevance to clinical practice are discussed.

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Michael Karsy, Jian Guan, Walavan Sivakumar, Jayson A. Neil, Meic H. Schmidt and Mark A. Mahan

Genetic alterations in the cells of intradural spinal tumors can have a significant impact on the treatment options, counseling, and prognosis for patients. Although surgery is the primary therapy for most intradural tumors, radiochemothera-peutic modalities and targeted interventions play an ever-evolving role in treating aggressive cancers and in addressing cancer recurrence in long-term survivors. Recent studies have helped delineate specific genetic and molecular differences between intradural spinal tumors and their intracranial counterparts and have also identified significant variation in therapeutic effects on these tumors. This review discusses the genetic and molecular alterations in the most common intradural spinal tumors in both adult and pediatrie patients, including nerve sheath tumors (that is, neurofibroma and schwannoma), meningioma, ependymoma, astrocytoma (that is, low-grade glioma, anaplastic astrocytoma, and glioblastoma), hemangioblastoma, and medulloblastoma. It also examines the genetics of metastatic tumors to the spinal cord, arising either from the CNS or from systemic sources. Importantly, the impact of this knowledge on therapeutic options and its application to clinical practice are discussed.

Full access

Jian Guan, Michael Karsy, Andrea A. Brock, Ilyas M. Eli, Holly K. Ledyard, Gregory W. J. Hawryluk and Min S. Park

OBJECTIVE

Hypovitaminosis D is highly prevalent among the general population. Studies have shown an association between hypovitaminosis D and multiple negative outcomes in critical care patients, but there has been no prospective evaluation of vitamin D in the neurological critical care population. The authors examined the impact of vitamin D deficiency on in-hospital mortality and a variety of secondary outcomes.

METHODS

The authors prospectively collected 25-hydroxy vitamin D levels of all patients admitted to the neurocritical care unit (NCCU) of a quaternary-care center over a 3-month period. Demographic data, illness acuity, in-hospital mortality, infection, and length of hospitalization were collected. Univariate and multivariable logistic regression were used to examine the effects of vitamin D deficiency.

RESULTS

Four hundred fifteen patients met the inclusion criteria. In-hospital mortality was slightly worse (9.3% vs 4.5%; p = 0.059) among patients with deficient vitamin D (≤ 20 ng/dl). There was also a higher rate of urinary tract infection in patients with vitamin D deficiency (12.4% vs 4.2%; p = 0.002). For patients admitted to the NCCU on an emergency basis (n = 285), higher Simplified Acute Physiology Score II (OR 13.8, 95% CI 1.7–110.8; p = 0.014), and vitamin D deficiency (OR 3.0, 95% CI 1.0–8.6; p = 0.042) were significantly associated with increased in-hospital mortality after adjusting for other factors.

CONCLUSIONS

In the subset of patients admitted to the NCCU on an emergency basis, vitamin D deficiency is significantly associated with higher in-hospital mortality. Larger studies are needed to confirm these findings and to investigate the role of vitamin D supplementation in these patients.

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Jian Guan, Michael Karsy, William T. Couldwell, Richard H. Schmidt, Philipp Taussky, Joel D. MacDonald and Min S. Park

OBJECTIVE

The choice between treating and observing unruptured intracranial aneurysms is often difficult, with little guidance on which variables should influence decision making on a patient-by-patient basis. Here, the authors compared demographic variables, aneurysm-related variables, and comorbidities in patients who received microsurgical or endovascular treatment and those who were conservatively managed to determine which factors push the surgeon toward recommending treatment.

METHODS

A retrospective chart review was conducted of all patients diagnosed with an unruptured intracranial aneurysm at their institution between January 1, 2013, and January 1, 2016. These patients were dichotomized based on whether their aneurysm was treated. Demographic, geographic, socioeconomic, comorbidity, and aneurysm-related information was analyzed to assess which factors were associated with the decision to treat.

RESULTS

A total of 424 patients were identified, 163 who were treated surgically or endovascularly and 261 who were managed conservatively. In a multivariable model, an age < 65 years (OR 2.913, 95% CI 1.298–6.541, p = 0.010), a lower Charlson Comorbidity Index (OR 1.536, 95% CI 1.274–1.855, p < 0.001), a larger aneurysm size (OR 1.176, 95% CI 1.100–1.257, p < 0.001), multiple aneurysms (OR 2.093, 95% CI 1.121–3.907, p = 0.020), a white race (OR 2.288, 95% CI 1.245–4.204, p = 0.008), and living further from the medical center (OR 2.125, 95% CI 1.281–3.522, p = 0.003) were all associated with the decision to treat rather than observe.

CONCLUSIONS

Whereas several factors were expected to be considered in the decision to treat unruptured intracranial aneurysms, including age, Charlson Comorbidity Index, aneurysm size, and multiple aneurysms, other factors such as race and proximity to the medical center were unanticipated. Further studies are needed to identify such biases in patient treatment and improve treatment delineation based on patient-specific aneurysm rupture risk.