Extracellular Vesicles in Molecular Diagnostics: An Overview with a Focus on CNS Diseases.

All known cells continuously release nanoscale lipid membrane-enclosed packets. These packets, termed extracellular vesicles (EVs), bear the signature of their cells of origin. These vesicles can be detected in just about every type of biofluid tested, including blood, urine, and cerebrospinal fluid. The majority comes from normal cells, but disease cells also release them. There is a great interest in collecting and analyzing EVs in biofluids as diagnostics for a wide spectrum of central nervous system diseases. Here, we will review the state of central nervous system EV research in terms of molecular diagnostics and biomarkers.

Diagnostic Accuracy of PET, SPECT, and Arterial Spin-Labeling in Differentiating Tumor Recurrence from Necrosis in Cerebral Metastasis after Stereotactic Radiosurgery.

BACKGROUND AND PURPOSE: Radiographic assessment of cerebral metastasis after stereotactic radiosurgery remains a major challenge in neuro-oncology. It is often difficult to distinguish tumor progression from radiation necrosis in this setting using conventional MR imaging. The objective of this study was to compare the diagnostic sensitivity and specificity of different functional imaging modalities for detecting tumor recurrence after stereotactic radiosurgery. MATERIALS AND METHODS: We retrospectively reviewed patients treated between 2007 and 2010 and identified 14 patients with cerebral metastasis who had clinical or radiographic progression following stereotactic radiosurgery and were imaged with arterial spin-labeling, FDG-PET, and thallium SPECT before stereotactic biopsy. Diagnostic accuracy, specificity, sensitivity, positive predictive value, and negative predictive value were calculated for each imaging technique by using the pathologic diagnosis as the criterion standard. RESULTS: Six patients (42%) had tumor progression, while 8 (58%) developed radiation necrosis. FDG-PET and arterial spin-labeling were equally sensitive in detecting tumor progression (83%). However, the specificity of arterial spin-labeling was superior to that of the other modalities (100%, 75%, and 50%, respectively). A combination of modalities did not augment the sensitivity, specificity, positive predictive value, or negative predictive value of arterial spin-labeling. CONCLUSIONS: In our series, arterial spin-labeling positivity was closely associated with the pathologic diagnosis of tumor progression after stereotactic radiosurgery. Validation of this finding in a large series is warranted.

Iterative probabilistic voxel labeling: automated segmentation for analysis of The Cancer Imaging Archive glioblastoma images.

BACKGROUND AND PURPOSE: Robust, automated segmentation algorithms are required for quantitative analysis of large imaging datasets. We developed an automated method that identifies and labels brain tumor-associated pathology by using an iterative probabilistic voxel labeling using k-nearest neighbor and Gaussian mixture model classification. Our purpose was to develop a segmentation method which could be applied to a variety of imaging from The Cancer Imaging Archive. MATERIALS AND METHODS: Images from 2 sets of 15 randomly selected subjects with glioblastoma from The Cancer Imaging Archive were processed by using the automated algorithm. The algorithm-defined tumor volumes were compared with those segmented by trained operators by using the Dice similarity coefficient. RESULTS: Compared with operator volumes, algorithm-generated segmentations yielded mean Dice similarities of 0.92 ± 0.03 for contrast-enhancing volumes and 0.84 ± 0.09 for FLAIR hyperintensity volumes. These values compared favorably with the means of Dice similarity coefficients between the operator-defined segmentations: 0.92 ± 0.03 for contrast-enhancing volumes and 0.92 ± 0.05 for FLAIR hyperintensity volumes. Robust segmentations can be achieved when only postcontrast T1WI and FLAIR images are available. CONCLUSIONS: Iterative probabilistic voxel labeling defined tumor volumes that were highly consistent with operator-defined volumes. Application of this algorithm could facilitate quantitative assessment of neuroimaging from patients with glioblastoma for both research and clinical indications.

Prognostic factors for stereotactic radiosurgery-treated patients with cerebral metastasis: implications on randomised control trial design and inter-institutional collaboration.

INTRODUCTION: Defining key prognostic factors for patients with cerebral metastases who underwent stereotactic radiosurgery (SRS) treatment will greatly facilitate future clinical trial designs. METHODS: We adopted a two-phase study design where results from one cohort were validated in a second independent cohort. The exploratory analysis reviewed the survival outcomes of 1017 consecutive patients (with 3610 metastases) who underwent Gamma radiosurgery at the University of California, San Diego (UCSD)/San Diego Gamma Knife Center (SDGKC). Multivariate analysis was performed to identify prognostic factors. Results were validated using data derived from 2519 consecutive patients (with 17,498 metastases) treated with SRS at the Katsuta Hospital. RESULTS: For the SDGKC cohort, the median overall survival of patients following SRS was 7 months. Two year follow-up data were available for 85% of the patients. Multivariate analysis found that patient age, Karnofsky Performance Status, systemic cancer status, tumour histology, number of metastasis and cumulative tumour volume independently associated with overall survival (p<0.001). All statistical associations were validated by multivariate analysis of data derived from the Katsuta Hospital cohort. CONCLUSIONS: This is the first integrated study that defined prognostic factors for SRS-treated patients with cerebral metastases using an inter-institutional validation study design. The work establishes a model for collaborative interactions between large volume centers and provides prognostic variables that should be incorporated into future clinical trial design.

Recovery of white matter tracts in regions of peritumoral FLAIR hyperintensity with use of restriction spectrum imaging.

BACKGROUND AND PURPOSE: DTI is being increasingly used to visualize critical white matter tracts adjacent to brain tumors before neurosurgical resection. However, brain tumors, particularly high-grade gliomas, are typically surrounded by regions of FLAIR hyperintensity that include edema, which increase isotropic diffusion, degrading the ability of standard DTI to uncover orientation estimates within these regions. We introduce a new technique, RSI, which overcomes this limitation by removing the spherical, fast diffusion component introduced by edema, providing better analysis of white matter architecture. MATERIALS AND METHODS: A total of 10 patients with high-grade gliomas surrounded by FLAIR-HI that at least partially resolved on follow-up imaging were included. All patients underwent RSI and DTI at baseline (FLAIR-HI present) and at follow-up (FLAIR-HI partially resolved). FA values obtained with RSI and DTI were compared within regions of FLAIR-HI and NAWM at both time points. RESULTS: RSI showed higher FA in regions of FLAIR-HI and NAWM relative to DTI, reflecting the ability of RSI to specifically measure the slow, restricted volume fraction in regions of edema and NAWM. Furthermore, a method by time interaction revealed that FA estimates increased when the FLAIR-HI resolved by use of standard DTI but remained stable with RSI. Tractography performed within the region of FLAIR-HI revealed the superior ability of RSI to track fibers through severe edema relative to standard DTI. CONCLUSIONS: RSI improves the quantification and visualization of white matter tracts in regions of peritumoral FLAIR-HI associated with edema relative to standard DTI and may provide a valuable tool for neurosurgical planning.

Four wishes for Aubrey.

In the critical care environment, what begins as cure-oriented and life-extending treatment may become unsuccessful in overcoming the patient's increasingly complex pathophysiology. A case from the neonatal intensive care unit is presented and used to elaborate upon care transitions toward palliative and supportive care that can be rendered in the hospital, at home or in a hospice facility. Successful transitions may rest upon anticipatory guidance by the primary physician and team, or a consultant, to facilitate and enable parents and team members alike in addressing the hard realities that cure, or even successful ICU discharge, is unlikely. A simple mechanism of addressing and accommodating a family's wishes is provided.

Maternal and neonatal characteristics of extremely low birth weight infants who die in the first day of life.

OBJECTIVE: To determine changes over time in the characteristics of early extremely low birth weight non-survivors (E-ELBW-NS), maternal characteristics and perinatal management, and the documentation of perinatal consultations. STUDY DESIGN: We conducted a chart review of infants <750 g who died within 24 h divided into two epochs: 1 January 1995 to 31 December 1999 and 1 January 2000 to 31 December 2005. Maternal and neonatal characteristics, delivery room resuscitation, post-resuscitation care, and documentation of resuscitation and perinatal counseling were examined. RESULT: A total of 138 infants met inclusion criteria. During Epoch 2, there was an increase in black, small for gestational age infants and prior maternal preterm delivery, and decreased incidences of tocolysis and chorioamnionitis. Also, a trend toward more hemolysis elevated liver enzymes and low platelet syndrome and decreased prenatal care existed. Perinatal consultations increased in both number and quality with time. CONCLUSION: There has been a shift in racial distribution toward more black infants in the second epoch perhaps reflecting disparities in care. Otherwise, demographics and management of E-ELBW-NS have changed minimally. There has been a significant improvement in the documentation of perinatal consultations.

Families' views upon experiencing change in the neonatal intensive care unit environment: from the 'baby barn' to the private room.

BACKGROUND: Parents whose newborns were cared for in the old neonatal intensive care unit (NICU) environment and then moved to the new NICU environment describe their impressions of the impact upon their infant's care, information access and support, of the two care settings. OBJECTIVES: To determine the perceptions of parents in the NICU regarding noise, light, space, access to caregivers and personal privacy as they experience both old and new NICU environments in the continuum of care for their infant. METHODS: In the first 9 months after moving into the new private room NICU, a convenience sampling of parents was voluntarily administered a 20-question Likert scale survey addressing length of stay (LOS) in the respective NICU environment, environmental stimuli, access to caregivers, access to information and personal privacy. Scores reflect frequency of perceptions as never=1, sometimes=2, usually=3 and always=4. RESULTS: The responses of 53 parents are reported. This represents 10% of admissions to the private room NICU during the 9-month sampling time. Fifty-nine percent had LOS of

Necrotizing enterocolitis associated with in utero and breast milk exposure to the selective serotonin reuptake inhibitor, escitalopram.

A term neonate presenting with necrotizing enterocolitis following in utero and breast milk exposure to the newest serotonin selective reuptake inhibitor, escitalopram, is described.

Patterns of exercise across the cancer trajectory in brain tumor patients.

BACKGROUND: Exercise may represent a supportive intervention that may complement existing neurooncologic therapies and address a multitude of therapy-induced debilitating side effects in patients with brain tumors. Given the limited evidence, the authors conducted a survey to examine the exercise patterns of brain tumor patients across the cancer trajectory. METHODS: Using a cross-sectional design, 386 brain tumor patients who received treatment at the Brain Tumor Center at Duke University were sent a questionnaire that assessed self-reported exercise behavior prior to diagnosis, during adjuvant therapy, and after the completion of therapy. RESULTS: The response rate was 28% (106 of 383 patients). Descriptive analyses indicated that 42%, 38%, and 41% of participants, respectively, met national exercise prescription guidelines prior to diagnosis, during treatment, and after the completion of adjuvant therapy. Repeated measures analyses indicated no significant changes in the majority of exercise behavior outcomes over the cancer trajectory. However, exploratory analyses indicated that males and younger participants may be at the greatest risk of reducing exercise levels after a brain tumor diagnosis. These analyses remained unchanged after controlling for relevant demographic and medical covariates. CONCLUSIONS: A relatively high percentage of brain tumor patients are exercising at recommended levels across the cancer trajectory. Moreover, these patients have unique exercise patterns that may be modified by select demographic variables. This preliminary study provides important informative data for future studies examining the potential role of exercise in patients diagnosed with neurologic malignancies.

SSRI and statin use increases the risk for vasospasm after subarachnoid hemorrhage.

BACKGROUND: Use of medications with vasoconstrictive or vasodilatory effects can potentially affect the risk for vasospasm after aneurysmal subarachnoid hemorrhage (SAH). METHODS: Using International Classification of Diseases-9 diagnostic codes followed by medical record review, the authors identified 514 patients with SAH admitted between 1995 and 2003 who were evaluated for vasospasm between days 4 and 14. The authors determined risks for vasospasm, symptomatic vasospasm, and poor clinical outcomes in patients with documented pre-hemorrhagic use of calcium channel blockers, beta-receptor blockers, ACE inhibitors, aspirin, selective serotonin reuptake inhibitors (SSRIs), non-SSRI vasoactive antidepressants, or statins. RESULTS: Vasospasm developed in 62%, and symptomatic vasospasm in 29% of the cohort. On univariate analysis, the risk for all vasospasm tended to increase in patients taking SSRIs (p = 0.09) and statins (p = 0.05); SSRI use increased the risk for symptomatic vasospasm (p = 0.028). The Cochran-Armitage trend test showed that the proportion of patients taking SSRIs and statins increased significantly across three worsening categories (none, asymptomatic, symptomatic) of vasospasm. Logistic regression analysis showed that SSRI use tended to predict all vasospasm (O.R. 2.01 [0.91 to 4.45]), and predicted symptomatic vasospasm (O.R. 1.42 [1.06 to 4.33]). Statin exposure increased the risk for vasospasm (O.R. 2.75 [1.16 to 6.50]), perhaps from abrupt statin withdrawal (O.R. 2.54 [0.78 to 8.28]). Age < 50 years, Hunt-Hess grade 4 or 5, and Fisher Group 3 independently predicted all vasospasm, symptomatic vasospasm, poor discharge clinical status, and death. CONCLUSION: Selective serotonin reuptake inhibitor and statin users have a higher risk for subarachnoid hemorrhage-related vasospasm. Whether the underlying disease indication, direct actions, or rebound effects from abrupt drug withdrawal account for the associated risk warrants further investigation.

Computed tomographic demonstrated infarcts after surgical and endovascular treatment of aneurysmal subarachnoid hemorrhage.

BACKGROUND: Cerebral infarction is a sequela of vasospasm. Other etiologies for infarction after subarachnoid hemorrhage (SAH), however, have not been well-studied. To determine the incidence and etiologies for infarction after SAH, we reviewed the head CT scans of all SAH patients at our center from 1993-2000. METHODS: From 1993-2000, 679 consecutive patients were admitted with SAH, of which 619 patients underwent surgical or endovascular treatment. Two reviewers examined the head CT scans of all 619 patients for new infarct. Clinical outcome was collected from a prospective database. FINDINGS: 505 patients were treated with surgical clipping; 114 with endovascular coiling. There were CT findings of new infarct in 189 patients (30%): 140 in the surgical group (28%) and 49 in the endovascular group (43%). The etiologies for infarct in the surgical group were vasospasm 79 (15%), perforator occlusion 40 (8%), large vessel occlusion 14 (3%), elevated intracranial pressure 4 (1%), thromboembolism 2 (0.4%), and systemic hypotension 1 (0.2%). Infarcts in the endovascular group were due to vasospasm 20 (18%), thromboembolism 12 (11%), large vessel occlusion/dissection 9 (8%), elevated intracranial pressure 4 (4%), perforator occlusion 3 (3%), and systemic hypotension 1 (1%). Hunt Hess Grade (P < 0.001), Fisher Score (P < 0.0001), and MGH Grade (P < 0.001) were significantly associated with CT-demonstrated infarct. There was no significant difference in incidence of CT-infarcts when the period 1993-1996 was compared to 1997-2000. CONCLUSIONS: Despite advances in the treatment of SAH, there is still a significant incidence of associated radiographic infarcts. Hunt Hess Grade, Fisher Score, and MGH Grade were significantly associated with CT-demonstrated infarct.

Incidence of residual intracranial AVMs after surgical resection and efficacy of immediate surgical re-exploration.

BACKGROUND: The true incidence of residual lesions after surgical resection of AVMs is not well documented in the literature. Partial surgical resection is thought to not confer any improvement over the natural history risk of hemorrhage of AVMs, and in certain cases may actually increase the risk of hemorrhage. Over the past 11 years, we have adopted a policy of immediate postoperative angiography with immediate surgical re-exploration if a residual lesion is seen. The purpose of the present study was to review our experience to determine the incidence of residual lesions and subsequent outcome. METHODS: From June 1991 to June 2002, 324 patients underwent craniotomy and surgical AVM resection. As per protocol, all patients underwent immediate postoperative angiography. We have a protocol for immediate surgical re-exploration if a residual lesion is seen on postoperative angiographic exam. FINDINGS: There were total six patients (1.8% of patients operated with intracranial AVMs) with residual lesions on postoperative angiography. All six patients underwent immediate surgical re-exploration with complete 100% obliteration; two patients required two re-exploration procedures. There was one operative complication: posterior cerebral artery and superior cerebellar artery infarcts after re-exploration of residual lesion after surgical resection of a large occipito-temperal-parietal AVM. There were no other morbidities and no mortalities. CONCLUSIONS: The incidence of residual lesions seen on postoperative angiography after AVM surgery at an experienced center is 1.8%. Because of the potential imminent danger of hemorrhage from a residual lesion, we recommend a policy of immediate postoperative angiography (or intraoperative angiography if image quality is satisfactory) for all AVM surgery and early surgical re-exploration if a residual lesion is seen.

Comfort/palliative care guidelines for neonatal practice: development and implementation in an academic medical center.

OBJECTIVE: To report the multidisciplinary developmental process of a comfort care guideline for the neonatal intensive care unit (NICU) addressing palliative care measures in a tertiary academic medical center. The guideline was developed to be (1) practical, (2) family-centered, (3) respectful of the infant patient, and (4) educational. METHODS: A consensus-building process involving medical, nursing, administrative, and ancillary professional staff integral to the NICU and Obstetrics units using naturalistic inquiry. RESULTS: An approved hospital guideline was formulated and implemented over a 16-month period. It described candidates for comfort care, the locale for such care to be rendered, and the construct of essential services to the infant and family. Early reports attest to staff acceptance and it is currently incorporated into trainee education. CONCLUSION: Clinically practical guidelines, comprehensive in their scope of providing comfort care to newborns with life-limiting conditions, can be institutionally derived and locally implemented for both consistency in patient care and educational value for staff and trainees.

Combined surgical and endovascular techniques of flow alteration to treat fusiform and complex wide-necked intracranial aneurysms that are unsuitable for clipping or coil embolization.

OBJECT: Certain intracranial aneurysms, because of their fusiform or complex wide-necked structure, giant size, or involvement with critical perforating or branch vessels. are unamenable to direct surgical clipping or endovascular coil treatment. Management of such lesions requires alternative or novel treatment strategies. Proximal and distal occlusion (trapping) is the most effective strategy. In lesions that cannot be trapped, alteration in blood flow to the "inflow zone," the site most vulnerable to aneurysm growth and rupture, is used. METHODS: From 1991 to 1999 the combined neurosurgical-neuroendovascular team at the Massachusetts General Hospital (MGH) managed 48 intracranial aneurysms that could not be clipped or occluded. Intracavernous internal carotid artery aneurysms were excluded from this analysis. By applying a previously described aneurysm rupture risk classification system (MGH Grades 0-5) based on the age of the patient, aneurysm size, Hunt and Hess grade, Fisher grade, and whether the aneurysm was a giant lesion located in the posterior circulation, the authors found that a significant number of patients were at moderate risk (MGH Grade 2; 31.3% of patients) and at high risk (MGH Grades 3 or 4; 22.9%) for treatment-related morbidity. The lesions were treated using a variety of strategies--surgical, endovascular, or a combination of modalities. Aneurysms that could not be trapped or occluded were treated using a paradigm of flow alteration, with flow redirected from either native collateral networks or from a surgically performed vascular bypass. Overall clinical outcomes were determined using the Glasgow Outcome Scale (GOS). A GOS score of 5 or 4 was achieved in 77.1%, a GOS score of 3 or 2 in 8.3%, and death (GOS 1) occurred in 14.6% of the patients. Procedure-related complications occurred in 27.1% of cases; the major morbidity rate was 6.3% and the mortality rate was 10.4%. Three patients experienced aneurysmal hemorrhage posttreatment; in two patients this event proved to be fatal. Aneurysms with MGH Grades 0, 1, 2, 3, and 4 were associated with favorable outcomes (GOS scores of 5 or 4) in 100%, 92.8%, 71.4%, 50%, and 0% of instances, respectively. CONCLUSIONS: Despite a high incidence of transient complications, intracranial aneurysms that cannot be clipped or occluded require alternative surgical and endovascular treatment strategies. In those aneurysms that cannot safely be trapped or occluded, one approach is the treatment strategy of flow alteration.

Results after surgical and endovascular treatment of paraclinoid aneurysms by a combined neurovascular team.

OBJECTIVE: Advances in surgical and endovascular techniques have improved treatment for paraclinoid aneurysms. A combined surgical and endovascular team can formulate individualized treatment strategies for patients with paraclinoid aneurysms. Patients who are considered to be at high surgical risk can be treated endovascularly to minimize morbidity. We reviewed the clinical and radiographic outcomes of 238 paraclinoid aneurysms treated by our combined surgical and endovascular unit. METHODS: From 1991 to 1999, the neurovascular team treated 238 paraclinoid aneurysms in 216 patients at the Massachusetts General Hospital. The modality of treatment for each aneurysm was chosen based on anatomic and clinical risk factors, with endovascular treatment offered to patients considered to have higher surgical risks. One hundred eighty aneurysms were treated by direct surgery, 57 were treated by endovascular occlusion, and one was treated by surgical extracranial-intracranial bypass and endovascular internal carotid artery balloon occlusion. Locations were transitional, 12 (5%); carotid cave, 11 (5%); ophthalmic, 131 (55%); posterior carotid wall, 38 (16%); and superior hypophyseal 46 (19%). Lesions contained completely within the cavernous sinus were excluded from this analysis. RESULTS: Using the Glasgow Outcome Scale (GOS), overall clinical outcomes were excellent or good (GOS 5 or 4), 86%; fair (GOS 3), 7%; poor (GOS 2), 4%; and death (GOS 1), 3%. Among the surgically treated patients, 90% experienced excellent or good outcomes (GOS 5 or 4), 6% had fair outcomes (GOS 3), 2% had poor outcomes (GOS 2), and 3% died (GOS 1). Among the endovascularly treated patients, 74% had excellent or good outcomes (GOS 5 or 4), 12% had fair outcomes (GOS 3), 10% had poor outcomes (GOS 2), and 4% died (GOS 1). The overall major and minor complication rate from surgery was 29%, with a 6% surgery-related permanent morbidity rate and a mortality rate of 0%. The overall major and minor complication rate from endovascular treatment was 21%, with a 3% endovascular-related permanent morbidity rate and a 2% mortality rate. Visual outcomes for patients who presented with visual symptoms were as follows: improved, 69%; no change, 25%; worsened, 6%; and new visual deficits, 3%. In general, angiographic efficacy was lower in the endovascular treatment group. CONCLUSION: A combined team approach of direct surgery and endovascular coiling can lead to good outcomes in the treatment for paraclinoid aneurysms, including high-risk lesions that might not have been treated in previous surgical series.