Genome-wide association studies: a powerful tool for neurogenomics.

As their power and utility increase, genome-wide association (GWA) studies are poised to become an important element of the neurosurgeon's toolkit for diagnosing and treating disease. In this paper, the authors review recent findings and discuss issues associated with gathering and analyzing GWA data for the study of neurological diseases and disorders, including those of neurosurgical importance. Their goal is to provide neurosurgeons and other clinicians with a better understanding of the practical and theoretical issues associated with this line of research. A modern GWA study involves testing hundreds of thousands of genetic markers across an entire genome, often in thousands of individuals, for any significant association with a particular disease. The number of markers assayed in a study presents several practical and theoretical issues that must be considered when planning the study. Genome-wide association studies show great promise in our understanding of the genes underlying common neurological diseases and disorders, as well as in leading to a new generation of genetic tests for clinicians.

Electrical forepaw stimulation during reversible forebrain ischemia decreases infarct volume.

BACKGROUND AND PURPOSE: Functional stimulation is accompanied by increases in regional cerebral blood flow which exceed metabolic demands under normal circumstances, but it is unknown whether functional stimulation is beneficial or detrimental in the setting of acute ischemia. The aim of this study was to determine the effect of forepaw stimulation during temporary focal ischemia on neurological and tissue outcome in a rat model of reversible focal forebrain ischemia. METHODS: Sprague-Dawley rats were prepared for temporary occlusion of the right middle cerebral artery (MCA) using the filament model. Cerebral blood flow in the MCA territory was continuously monitored with a laser-Doppler flowmeter. Subdermal electrodes were inserted into the dorsal forepaw to stimulate either the forepaw ipsilateral or contralateral to the occlusion starting 1 minute into ischemia and continuing throughout the ischemic period. A neurological evaluation was undertaken after 24 hours of reperfusion, and animals were then euthanized and brain slices stained with 2,3,5-triphenyltetrazolium chloride. Cortical and striatal damage was measured separately. RESULTS: The cortical and striatal infarct volumes were both significantly reduced in the contralateral stimulated group compared with the ipsilateral stimulated group (48% total reduction). There were no statistically significant differences in the neurobehavioral scores between the 2 groups, or in the laser-Doppler flow measurements from the MCA core. CONCLUSIONS: Functional stimulation of ischemic tissue may decrease tissue damage and improve outcome from stroke. Although the precise mechanism of this effect remains to be determined, functional stimulation could readily be translated to clinical practice.

Shunts in normal-pressure hydrocephalus: do we place too many or too few?

OBJECT: The average 65-year-old patient with moderate dementia can look forward to only 1.4 quality-adjusted life years (QALYs), that is, longevity times quality of life. Some of these patients suffer from normal-pressure hydrocephalus (NPH) and respond dramatically to shunt insertion. Currently, however, NPH cannot be diagnosed with certainty. The authors constructed a Markov decision analysis model to predict the outcome in patients with NPH treated with and without shunts. METHODS: Transition probabilities and health utilities were obtained from a review of the literature. A sensitivity analysis and Monte Carlo simulation were applied to test outcomes over a wide range of parameters. Using shunt response and complication rates from the literature, the average patient receiving a shunt would gain an additional 1.7 QALYs as a result of automatic shunt insertion. Even if 50% of patients receiving a shunt have complications, the shunt response rate would need to be less than 5% for empirical shunt insertion to do more harm than good. Authors of most studies have reported far better statistics. CONCLUSIONS: In summary, many more patients with suspected NPH should be considered for shunt insertion.

Screening tests for normal-pressure hydrocephalus: sensitivity, specificity, and cost.

OBJECT: Many tests have been proposed to help choose candidates for shunt insertion in cases of suspected normal-pressure hydrocephalus (NPH). It is unclear what sensitivity and specificity a prospective test must have to improve outcomes, compared with the results of automatic shunt insertion. METHODS: The authors adapted the decision analysis model used in a companion article to allow for application of a screening test. Using the reported sensitivities and specificities of several such tests, they evaluated the effects such tests would have on the expected outcome of an average 65-year-old patient with moderate dementia. They also evaluated the cost-effectiveness of a theoretical screening test with superior sensitivity and specificity. CONCLUSIONS: Although external lumbar drainage comes quite close, none of the screening tests reported to date have sufficient sensitivity and specificity to improve expected outcome in an average candidate, compared with the results of automatic shunt placement in cases of suspected NPH. In addition, even a theoretically improved test would need to be considerably less expensive than prolonged lumbar drainage to be cost-effective in clinical practice.

Recurrent late cerebral necrosis with aggressive characteristics after radiosurgical treatment of an arteriovenous malformation. Case report.

/Late cerebral radiation necrosis usually occurs within 3 years of stereotactic radiosurgery. The authors report on a case of recurrent radiation necrosis with rapid clinical deterioration and imaging findings resembling those of a malignant glioma. This 68-year-old man, who had a history of a left posterior temporal and thalamic arteriovenous malformation (AVM) treated with linear accelerator radiosurgery 13 years before presentation and complicated by radiation necrosis 11 years before presentation, exhibited new-onset mixed aphasia, right hemiparesis, and right hemineglect. Imaging studies demonstrated hemorrhage and an enlarging, heterogeneously enhancing mass in the region of the previously treated AVM. The patient was treated medically with corticosteroid agents, and stabilized temporarily. Unfortunately, his condition worsened precipitously soon thereafter, requiring the placement of a shunt for relief of obstructive hydrocephalus. Further surgical intervention was offered, but the patient's family opted for hospice care instead. The patient died 10 weeks after initially presenting to the authors' institution, and the results of an autopsy demonstrated radiation necrosis. Symptomatic radiation necrosis can occur more than a decade after stereotactic radiosurgery, necessitating patient follow up during a longer period of time than currently practiced. Furthermore, there is a need for more careful reporting on the natural history of such cases to clarify the pathogenesis of very late and recurrent radiation necrosis after radiosurgery and to define patient groups with a higher risk for these entities.

Return to contact sports after spinal surgery.

Decisions regarding the return of injured athletes to contact sports after spinal surgery can be complicated. The authors offer a brief overview of the return-to-play guidelines used successfully at their institution for the past two decades when caring for professional and amateur athletes after spinal surgery.

A Comparative Study of the Molecular Characteristics of Familial Gliomas and Other Cancers.

BACKGROUND: Familial cancers are those that co-occur among first-degree relatives without showing Mendelian patterns of inheritance. MATERIALS AND METHODS: In this analysis, we compare the genomic characteristics of familial and sporadic cancers, with a focus on low-grade gliomas (LGGs) using sequence and expression data from the Cancer Genome Atlas. RESULTS: Familial cancers show similar genomic and molecular biomarker profiles to sporadic cancers, consistent with the similarity in their clinical features. There are no statistically significant differences among somatic mutation, copy number variant, or gene expression patterns between familial and sporadic cancers; methylation profiles are the only class of molecular data to show significant differences. CONCLUSION: Familial cancers are likely driven by multiple, individually weak contributions to familiality (i.e. large numbers of alleles and/or shared environmental risks). Consequently, these risk factors tend to be obscured by stronger confounding variables such as clinical or molecular variation among cancer subtypes.

Molecular Predictors of Long-Term Survival in Glioblastoma Multiforme Patients.

Glioblastoma multiforme (GBM) is the most common and aggressive adult primary brain cancer, with <10% of patients surviving for more than 3 years. Demographic and clinical factors (e.g. age) and individual molecular biomarkers have been associated with prolonged survival in GBM patients. However, comprehensive systems-level analyses of molecular profiles associated with long-term survival (LTS) in GBM patients are still lacking. We present an integrative study of molecular data and clinical variables in these long-term survivors (LTSs, patients surviving >3 years) to identify biomarkers associated with prolonged survival, and to assess the possible similarity of molecular characteristics between LGG and LTS GBM. We analyzed the relationship between multivariable molecular data and LTS in GBM patients from the Cancer Genome Atlas (TCGA), including germline and somatic point mutation, gene expression, DNA methylation, copy number variation (CNV) and microRNA (miRNA) expression using logistic regression models. The molecular relationship between GBM LTS and LGG tumors was examined through cluster analysis. We identified 13, 94, 43, 29, and 1 significant predictors of LTS using Lasso logistic regression from the somatic point mutation, gene expression, DNA methylation, CNV, and miRNA expression data sets, respectively. Individually, DNA methylation provided the best prediction performance (AUC = 0.84). Combining multiple classes of molecular data into joint regression models did not improve prediction accuracy, but did identify additional genes that were not significantly predictive in individual models. PCA and clustering analyses showed that GBM LTS typically had gene expression profiles similar to non-LTS GBM. Furthermore, cluster analysis did not identify a close affinity between LTS GBM and LGG, nor did we find a significant association between LTS and secondary GBM. The absence of unique LTS profiles and the lack of similarity between LTS GBM and LGG, indicates that there are multiple genetic and epigenetic pathways to LTS in GBM patients.

Activation-flow coupling during graded cerebral ischemia.

Most functional neuroimaging techniques rely on activation-flow coupling (AFC) to detect changes in regional brain function, but AFC responses may also be altered during pathophysiological conditions such as ischemia. To define the relationship between progressive ischemia and the AFC response, graded levels of cerebral blood flow reduction were produced using a rat compression ischemia model, and the cerebral hemodynamic response to forepaw stimulation was measured. Graded levels of cortical ischemia of the somatosensory cortex were induced in male Sprague-Dawley rats (n = 16) by compressing the intact dura with a 4-mm-diameter cylinder equipped with a laser-Doppler probe, combined with ipsilateral common carotid artery occlusion. At each level of CBF reduction, electric forepaw stimulation was conducted, and signal-averaged laser Doppler and evoked potential responses were recorded. A visible AFC response was present at all levels of CBF reduction (0-90% reduction from baseline), and the temporal characteristics of the response appeared largely preserved. However, the amplitude of the AFC response began to decline at levels of mild ischemia (10% flow reduction) and progressively decreased with further CBF reduction. The amplitude of the evoked response appeared to decrease in concert with the AFC amplitude and appeared to be equally sensitive to ischemia. AFC appears to be a sensitive marker for cerebral ischemia, and alterations in the AFC response occur at CBF reductions above the accepted thresholds for infarction. However, the AFC response is also preserved when flow is reduced below ischemic thresholds.

Intracranial capillary hemangioma: case report and review of the literature.

BACKGROUND: Capillary hemangiomas are benign vascular lesions that commonly present at birth or in early infancy on the face, scalp, back, or chest. The authors present an exceedingly rare case of an intracranial capillary hemangioma arising in an adult. Only 4 biopsy-proven cases have been reported in the pediatric population previous to this case report. CASE DESCRIPTION: A 31-year-old pregnant woman presented at 38 weeks of gestation with severe headaches, nausea, and vomiting. Imaging revealed an extra-axial mass lesion arising from the tentorium with both supra- and infratentorial components. The patient underwent a resection of her tumor, which was diagnosed as a capillary hemangioma by histopathologic examination. The patient required 2 further resections after the lesion exhibited a rapid regrowth from residual tumor in the left transverse sinus. The patient has remained free of disease 41 months out from her third surgery. CONCLUSIONS: Intracranial capillary hemangiomas are exceedingly rare entities, with a capability for rapid growth. When gross total resection cannot be achieved, these patients should be observed closely, and the use of adjuvant radiotherapy should be considered.

Spatiotemporal quantification of cerebral blood flow during functional activation in rat somatosensory cortex using laser-speckle flowmetry.

Laser-speckle flowmetry was used to characterize activation flow coupling after electrical somatosensory stimulation of forepaw and hindpaw in the rat. Quantification of functional activation was made with high transverse spatial (microm) and temporal (msec) resolution. Different activation levels and duration of stimulation were quantitatively investigated, and were in good agreement with previous laser-Doppler measurements. Interestingly, the magnitude but not the overall shape of the response was found to scale with stimulus amplitude and the distance from the activation centroid. The results provide new insights about the spatial characteristics of cerebral blood flow response to functional activation, and the method should lead to improved understanding of the coupling of neuronal activity and hemodynamics under normal and pathologic conditions.

What we research: survey of American Association of Neurological Surgeons and Congress of Neurological Surgeons member publications.

OBJECT: The goal of this study was to create a searchable database of research manuscripts authored by members of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons (AANS/CNS) to describe the nature and character of the research currently being undertaken by neurosurgeons. METHODS: Manuscripts published by all physician members listed in the 2001 AANS/CNS Membership Directory (6921 physicians) were gathered into a database through individual literature searches of the author name for the calendar year 2001. Duplicate publications were purged and the database was reviewed for accuracy. An internal verification of the database revealed a 4% underreporting rate. Statistics from the database were compiled and displayed with information about AANS/CNS members and their clinical activities. The AANS/CNS members published a total of 2748 research the manuscripts in 479 different journals during 2001. Thirty-eight percent of the manuscripts (1042 of 2748) were authored by US members and 62% (1706 of 2748) by non-US members. The focus of the majority of manuscripts included the areas of brain tumor (26%; 707 of 2748), vascular disease (20%; 558 of 2748), spine (10%; 282 of 2748), and trauma (8%; 233 of 2748). Sixty-nine percent of manuscripts (1897 of 2748) were retrospective and technical clinical studies, and of these 39% (744 of 1897) were case reports. Laboratory investigations made up 15% (414 of 2748) of all manuscripts, whereas prospective randomized clinical trials represented 1% (34 of 2748). CONCLUSIONS: The majority of AANS/CNS member manuscripts are authored by non-US members despite their small AANS/CNS representation. Most research is clinical, based on retrospective data, and includes a large number of case reports. A disparity exists between what neurosurgeons do clinically and both the quantity and subject of their research.

Pathophysiology of peripheral nerve injury: a brief review.

Clinicians caring for patients with brachial plexus and other nerve injuries must possess a clear understanding of the peripheral nervous system's response to trauma. In this article, the authors briefly review peripheral nerve injury (PNI) types, discuss the common injury classification schemes, and describe the dynamic processes of degeneration and reinnervation that characterize the PNI response.

Decision analysis to estimate cost effectiveness in neurosurgery.

Medical decisions often depend, in part, on cost-effectiveness concerns. Decision analysis is frequently used to help resolve these questions. Unfortunately, this technique has received little attention in neurosurgery. Using an example of moderate head injury, the authors illustrate the utility of this powerful tool in estimating the cost effectiveness of neurosurgical management options.

Prophylaxis for deep venous thrombosis in patients with craniotomies: a review.

Deep venous thrombosis (DVT) remains a source of significant morbidity and mortality in patients who undergo craniotomy procedures. Despite several studies in which the safety and efficacy of various prophylactic strategies were examined, there is still no consensus among clinicians. In this paper the authors review the literature with regard to epidemiological and pathophysiological features, screening methods, and prophylactic measures for DVT.

Anterior surgical management of single-level cervical disc disease: a cost-effectiveness analysis.

STUDY DESIGN: Cost-effectiveness analysis with decision analysis and meta-analysis. OBJECTIVE: To determine the relative cost-effectiveness of anterior cervical discectomy with fusion (with autograft, allograft, or spacers), anterior cervical discectomy without fusion (ACD), and cervical disc replacement (CDR) for the treatment of 1-level cervical disc disease. SUMMARY OF BACKGROUND DATA: There is debate as to the optimal anterior surgical strategy to treat single-level cervical disc disease. Surgical strategies include 3 techniques of anterior cervical discectomy with fusion (autograft, allograft, or spacer-assisted fusion), ACD, and CDR. Several controlled trials have compared these treatments but have yielded mixed results. Decision analysis provides a structure for making a quantitative comparison of the costs and outcomes of each treatment. METHODS: A literature search was performed and yielded 156 case series that fulfilled our search criteria describing nearly 17,000 cases. Data were abstracted from these publications and pooled meta-analytically to estimate the incidence of various outcomes, including index-level and adjacent-level reoperation. A decision analytic model calculated the expected costs in US dollars and outcomes in quality-adjusted life years for a typical adult patient with 1-level cervical radiculopathy subjected to each of the 5 approaches. RESULTS: At 5 years postoperatively, patients who had undergone ACD alone had significantly (P < 0.001) more quality-adjusted life years (4.885 ± 0.041) than those receiving other treatments. Patients with ACD also exhibited highly significant (P < 0.001) differences in costs, incurring the lowest societal costs ($16,558 ± $539). Follow-up data were inadequate for comparison beyond 5 years. CONCLUSION: The results of our decision analytic model indicate advantages for ACD, both in effectiveness and costs, over other strategies. Thus, ACD is a cost-effective alternative to anterior cervical discectomy with fusion and CDR in patients with single-level cervical disc disease. Definitive conclusions about degenerative changes after ACD and adjacent-level disease after CDR await longer follow-up. LEVEL OF EVIDENCE: 4.

Three-dimensional brain magnetic resonance imaging segmentation via knowledge-driven decision theory.

Brain tissue segmentation on magnetic resonance (MR) imaging is a difficult task because of significant intensity overlap between the tissue classes. We present a new knowledge-driven decision theory (KDT) approach that incorporates prior information of the relative extents of intensity overlap between tissue class pairs for volumetric MR tissue segmentation. The proposed approach better handles intensity overlap between tissues without explicitly employing methods for removal of MR image corruptions (such as bias field). Adaptive tissue class priors are employed that combine probabilistic atlas maps with spatial contextual information obtained from Markov random fields to guide tissue segmentation. The energy function is minimized using a variational level-set-based framework, which has shown great promise for MR image analysis. We evaluate the proposed method on two well-established real MR datasets with expert ground-truth segmentations and compare our approach against existing segmentation methods. KDT has low-computational complexity and shows better segmentation performance than other segmentation methods evaluated using these MR datasets.

Differentiating tumor recurrence from treatment necrosis: a review of neuro-oncologic imaging strategies.

Differentiating treatment-induced necrosis from tumor recurrence is a central challenge in neuro-oncology. These 2 very different outcomes after brain tumor treatment often appear similarly on routine follow-up imaging studies. They may even manifest with similar clinical symptoms, further confounding an already difficult process for physicians attempting to characterize a new contrast-enhancing lesion appearing on a patient's follow-up imaging. Distinguishing treatment necrosis from tumor recurrence is crucial for diagnosis and treatment planning, and therefore, much effort has been put forth to develop noninvasive methods to differentiate between these disparate outcomes. In this article, we review the latest developments and key findings from research studies exploring the efficacy of structural and functional imaging modalities for differentiating treatment necrosis from tumor recurrence. We discuss the possibility of computational approaches to investigate the usefulness of fine-grained imaging characteristics that are difficult to observe through visual inspection of images. We also propose a flexible treatment-planning algorithm that incorporates advanced functional imaging techniques when indicated by the patient's routine follow-up images and clinical condition.

An analysis of admissions from 155 United States hospitals to determine the influence of weather on stroke incidence.

Weather is the most frequently proposed factor driving apparent seasonal trends in stroke admissions. Here, we present the largest study of the association between weather and ischemic stroke in the USA to date. We consider admissions to 155 United States hospitals in 20 states during the five-year period from 2004 to 2008. The data set included 196,439 stroke admissions, which were classified as ischemic (n=98,930), hemorrhagic (n=18,960), or transient ischemic attack (n=78,549). Variations in stroke admissions were tested to determine if they tracked seasonal and transient weather patterns over the same time period. Using autocorrelation analyses, no significant seasonal changes in stroke admissions were observed over the study period. Using time-series analyses, no significant association was observed between any weather variable and any stroke subtype over the five-year study. This study suggests that seasonal associations between weather and stroke are highly confounded, and an association between weather and stroke is virtually non-existent. Therefore, previous studies reporting an association between specific weather patterns and stroke should be interpreted with caution.

Treatment course and outcomes following drug and alcohol-related traumatic injuries.

BACKGROUND: Alcohol and drug use is known to be a major factor affecting the incidence of traumatic injury. However, the ways in which immediate pre-injury substance use affects patients' clinical care and outcomes remains unclear. The goal of the present study is to determine the associations between pre-injury use of alcohol or drugs and patient injury severity, hospital course, and clinical outcome. MATERIALS AND METHODS: This study used more than 200,000 records from the National Trauma Data Bank (NTDB), which is the largest trauma registry in the United States. Incidents in the NTDB were placed into one of four classes: alcohol related, drug related, alcohol-and-drug related, and substance negative. Logistic regression models were used to determine comorbid conditions or treatment complications that were significantly associated with pre-injury substance use. Hospital charges were associated with the presence or absence of drugs and alcohol, and patient outcomes were assessed using discharge disposition as delimited by the NTDB. RESULTS: The rates of complications arising during treatment were 8.3, 10.9, 9.9 and 8.6 per one hundred incidents in the alcohol related, drug related, alcohol-and-drug related, and substance-negative classes, respectively. Regression models suggested that pre-injury alcohol use is associated with a 15% higher risk of infection, whereas pre-injury drug use is associated with a 30% higher risk of infection. Pre-injury substance use did not appear to significantly impact clinical outcomes following treatment for traumatic injury, however. CONCLUSION: This study suggests that pre-injury drug use is associated with a significantly higher complication rate. In particular, infection during hospitalization is a significant risk for both alcohol and drug related trauma visits, and drug-related trauma incidents are associated with increased risk for additional circulatory complications. Although drug and alcohol related trauma incidents are not associated with appreciably worse clinical outcomes, patients experiencing such complications are associated with significantly greater length of stay and higher hospitalization costs. Therefore significant benefits to trauma patients could be gained with enhanced surveillance for pre-injury substance use upon admission to the ED, and closer monitoring for infection or circulatory complications during their period of hospitalization.