Diagnosis and Management of Mild Traumatic Brain Injury in Children: A Systematic Review.

Importance: In recent years, there has been an exponential increase in the research guiding pediatric mild traumatic brain injury (mTBI) clinical management, in large part because of heightened concerns about the consequences of mTBI, also known as concussion, in children. The CDC National Center for Injury Prevention and Control's (NCIPC) Board of Scientific Counselors (BSC), a federal advisory committee, established the Pediatric Mild TBI Guideline workgroup to complete this systematic review summarizing the first 25 years of literature in this field of study. Objective: To conduct a systematic review of the pediatric mTBI literature to serve as the foundation for an evidence-based guideline with clinical recommendations associated with the diagnosis and management of pediatric mTBI. Evidence Review: Using a modified Delphi process, the authors selected 6 clinical questions on diagnosis, prognosis, and management or treatment of pediatric mTBI. Two consecutive searches were conducted on PubMed, Embase, ERIC, CINAHL, and SportDiscus. The first included the dates January 1, 1990, to November 30, 2012, and an updated search included December 1, 2012, to July 31, 2015. The initial search was completed from December 2012 to January 2013; the updated search, from July 2015 to August 2015. Two authors worked in pairs to abstract study characteristics independently for each article selected for inclusion. A third author adjudicated disagreements. The risk of bias in each study was determined using the American Academy of Neurology Classification of Evidence Scheme. Conclusion statements were developed regarding the evidence within each clinical question, and a level of confidence in the evidence was assigned to each conclusion using a modified GRADE methodology. Data analysis was completed from October 2014 to May 2015 for the initial search and from November 2015 to April 2016 for the updated search. Findings: Validated tools are available to assist clinicians in the diagnosis and management of pediatric mTBI. A significant body of research exists to identify features that are associated with more serious TBI-associated intracranial injury, delayed recovery from mTBI, and long-term sequelae. However, high-quality studies of treatments meant to improve mTBI outcomes are currently lacking. Conclusions and Relevance: This systematic review was used to develop an evidence-based clinical guideline for the diagnosis and management of pediatric mTBI. While an increasing amount of research provides clinically useful information, this systematic review identified key gaps in diagnosis, prognosis, and management.

Regional and total skeletal measurements in the early postmenopause.

In a cross-sectional study of 70 early postmenopausal women, regional bone measurements were compared with total body calcium (TBCa). Spinal and forearm trabecular bone were mainly related to age and time since menopause. In contrast, TBCa and forearm integral (cortical and trabecular) and cortical bone were unrelated to age, although the time since menopause also had some influence. Forearm integral and cortical bone measurements were quite well correlated with TBCa (r = 0.84 and 0.73, respectively, P less than 0.001). The correlation between spinal bone measurements and any of the forearm measurements, even purely trabecular bone, was weak (r less than 0.52, P less than 0.001). Our results show quite clearly that forearm bone measurements cannot be used to predict bone density in the vertebrae. Loss of ovarian function affects bone in general, and trabecular bone in particular. Bone measurements at specific anatomical sites are clearly necessary for studies of metabolic bone diseases and their response to treatment.

Evaluation of DFO-HOPO as an octadentate chelator for zirconium-89.

The future of 89Zr-based immuno-PET is reliant upon the development of new chelators with improved stability compared to the currently used deferoxamine (DFO). Herein, we report the evaluation of the octadentate molecule DFO-HOPO (3) as a suitable chelator for 89Zr and a more stable alternative to DFO. The molecule showed good potential for the future development of a DFO-HOPO-based bifunctional chelator (BFC) for the radiolabelling of biomolecules with 89Zr. This work broadens the selection of available chelators for 89Zr in search of improved successors to DFO for clinical 89Zr-immuno-PET.

Effects of 7 years of growth hormone replacement therapy in hypopituitary adults.

Short-term studies of GH replacement in adult hypopituitarism have usually demonstrated beneficial effects on body composition and circulating lipids, with neutral or occasionally adverse effects on glucose tolerance. Fasting hyperinsulinemia has been reported. GH effects on cardiac function have been variable. The effects of long-term GH therapy, taking into account the consequences of increasing age, are not fully known. Thirty-three hypopituitary, initially middle-aged adults were studied over a 7-yr period; 12 patients took GH therapy (mean, 0.7 mg daily) continuously (group A); 11 took GH for only 6-18 months, a minimum of 5 yr previously (group B); and 10 patients never received GH therapy (group C). Other pituitary replacement was maintained. Effects on anthropometry, body composition (by bioimpedance analysis, total body potassium, and dual energy x-ray absorptiometry), circulating lipids, glucose and insulin concentrations, cardiac 2-dimensional and Doppler echocardiography, and exercise tolerance were assessed before and after the treatment period. Continuous GH therapy had no significant effect on body weight, but it prevented the increase in waist circumference and waist to hip ratio that occurred in the patients without GH substitution (waist to hip ratio, group A, 0.87+/-0.08 at baseline, 0.85+/-0.09 at 7 yr; group B, 0.89+/-0.11 at baseline, 0.94+/-0.11 at 7 yr; P < 0.005 for GH effect; group C, 0.87+/-0.10 at baseline, 0.92+/-0.10 at 7 yr; P < 0.005 for GH effect). A GH-induced decrease in subscapular skinfold thickness was also observed. By bioimpedance analysis, GH therapy caused an increase in total body water and fat-free mass, and a decrease in the percent body fat. Although changes occurred with time in all groups, no significant additional GH therapy effects were observed on glucose tolerance, insulin concentrations, lipid levels, cardiac dimensions, echocardiographic diastolic function, or exercise tolerance. In conclusion, prolonged GH substitution in middle-aged hypopituitary adults causes a sustained improvement in body composition. Other benefits, e.g. on lipid levels and exercise tolerance, were not apparent at 7 yr when comparisons were made with GH-untreated hypopituitary controls. Potentially adverse effects on glucose tolerance and insulinemia did not develop with prolonged GH therapy.

The effects of 10 years of recombinant human growth hormone (GH) in adult GH-deficient patients.

The long term effects of GH replacement in adult GH-deficient (GHD) patients have not yet been clarified. We studied 21 GHD adults who originally took part in a randomized, double blind, placebo-controlled trial of GH treatment in 1987. After completion of that trial, 10 patients received continuous GH replacement for the subsequent 10 yr, whereas 11 did not. A group of 11 age- and sex-matched normal controls were also studied in 1987 and 1997. Lean body mass, as assessed by total body potassium measurement and computed tomography scanning of the dominant thigh, increased in the GH-treated group (P < 0.01 for both) only (P < 0.05 between groups for total body potassium). Low density lipoprotein cholesterol decreased in the GH-treated group (P < 0.05) only. Carotid intima media thickness was significantly greater (P < 0.05) in the untreated group than in the GH-treated group. Assessment of psychological well-being using the Nottingham Health Profile revealed improvement in overall score, energy levels, and emotional reaction in the GH-treated group compared with those in the untreated group (P < 0.02). In conclusion, GH treatment for 10 yr in GHD adults resulted in increased lean body and muscle mass, a less atherogenic lipid profile, reduced carotid intima media thickness, and improved psychological well-being.

Detection of thirty-second cognitive activations in single subjects with positron emission tomography: a new low-dose H2(15)O regional cerebral blood flow three-dimensional imaging technique.

Positron emission tomography regional CBF (rCBF) studies of cognitive processes have traditionally required 30-60 mCi of H2(15)O per scan and intersubject averaging to achieve statistical significance. However, intersubject anatomical, functional, and disease variability can make such an approach problematic. A new method that produces significant results in single subjects is presented. It is based upon high-sensitivity three-dimensional imaging and a "slow" bolus administration of < 15 mCi of H2(15)O per scan. The method is validated in four normal volunteers using control and auditory-language activation tasks with four scans per condition and statistical parametric mapping analysis. It is demonstrated that the rCBF distribution associated with the cognitive state is detected during the arrival of radiotracer in the brain. This occurs over 30 s and constitutes a critical temporal window during which stimulation should be performed. A 90-s acquisition time is found to produce results of greater significance than a 60-s acquisition time. The implications of the results and the functional neuroanatomical findings are discussed. This method is suitable for the study of individual functional neuroanatomy in many neuropsychological, pharmacologic, and symptom states in normal subjects and in patients with psychiatric and neurologic disorders.

Performance characteristics of a whole-body positron tomograph.

This paper describes an investigation of some of the important physical characteristics of a whole-body positron tomograph consisting of two rings of bismuth germanate detectors of dimensions 5.6 mm X 30 mm X 30 mm (512/ring). The resolution applicable to in vivo imaging is six mm or more, depending on radionuclide and reconstruction filter and is very uniform over the field of view normally used. Axial resolution can be varied by moving side collimation (maximum approximately 16 mm FWHM with interplane septa). A simple scheme has been devised to correct for loss of true coincidence events with varying count rate based on the total random and multiple coincidence rates. It is concluded that correction for scattered radiation should be implemented for reliable quantitation.

Generation of myocardial factor images directly from the dynamic oxygen-15-water scan without use of an oxygen-15-carbon monoxide blood-pool scan.

UNLABELLED: The measurement of regional myocardial blood flow (MBF) with H2(15)O and PET requires an additional C15O blood-pool scan for the purpose of region of interest (ROI) definition. This additional scan results in a substantially increased radiation dose, study duration and risk of movement artifacts. Therefore, a method was developed to generate myocardial factor images directly from the dynamic H2(15)O study without the need for a C15O scan. METHODS: The factor sinograms were generated by means of linear dimension reduction of the dynamic sinograms, where the required variate and covariate factors (myocardial and blood time-activity curves) were modeled from the lung time-activity curve. The factor images were generated by iterative reconstruction. RESULTS: No significant difference was found between MBF values from ROIs drawn on the traditional images (using the C15O scan) and those drawn on the factor images. CONCLUSION: It is possible to generate myocardial images directly from the dynamic H2(15)O study, so that the C15O scan can be omitted from MBF studies. The proposed method is robust and results in nearly optimal signal-to-noise ratios in the factor images.

Neutron-activation measurement of metabolic activity of sodium in the human hand.

Turnover of sodium in the human hand was studied by neutron activation. One hand of each subject was irradiated with a 1.5-rad dose of partially thermalized fast neutrons. The activity of 24Na was measured at intervals from 3 min to 48 hr after irradiation. The loss of sodium from the hand during this period can be described either by two exponentials or by a single power function. The latter description involves only two disposable factors compared with four in the former. The rate of loss of sodium was found, on the average, to be greater in patients suffering from bone disease than in normal subjects. Neutron activation is a powerful method for studying sodium turnover because the sodium atoms are labeled simultaneously and with equal probability, regardless of the turnover time of individual bodily compartments.

Metabolic activity of sodium, measured by neutron activation, in the hands of patients suffering from bone diseases: concise communication.

Turnover of sodium in the human hand was studied by neutron activation. Patients suffering from various metabolic abnormalities affecting the skeleton, who were undergoing routine neutron activation for the measurement of calcium, were investigated along with a group of healthy volunteers. Neutron activation labels the sodium atoms simultaneously and with equal probability regardless of the turnover time of individual body compartments. The loss of sodium can be described either by a sum of two exponentials or by a single power function. Distinctions between patients and normal subjects were not apparent from the exponential model but were brought out by the power function. The exponent of time in the latter is a measure of clearance rate. The mean values of this parameter in (a) a group of patients suffering from acromegaly: (b) a group including Paget's disease, osteoporosis, Cushing's disease, and hyperparathyroidism; and (c) a group of healthy subjects, were found to be significantly different from each other.

Beneficial effect of nitrates on myocardial glucose utilization in unstable angina pectoris.

Myocardial uptake of the glucose analog F-18-2-fluoro-2-deoxy-D-glucose (FDG) was assessed by positron emission tomography in 6 normal volunteers, 7 patients with chronic stable angina and 22 patients with unstable angina at rest in fasting conditions. Regional myocardial perfusion was assessed by rubidium-82. The study was repeated a few days later after intravenous infusion of isosorbide dinitrate. FDG uptake was similar in control subjects and patients with stable angina (0.023 +/- 0.032 vs 0.012 +/- 0.008 mol/ml/min, p less than 0.42) but was about 4-fold higher on the average in patients with unstable angina (0.084 +/- 0.047, p less than 0.01). The severity of coronary obstructions in stable and unstable angina patients was similar. The increased uptake involved the whole heart, including areas not distal to critically stenosed vessels; it was not associated with reduced myocardial perfusion and was not related to a recent episode of transient ischemia as assessed by symptoms and by Holter monitoring. After continuous infusion of nitrates, FDG uptake was consistently and significantly reduced toward normal levels both in areas perfused by critically stenosed coronary arteries and by noncritically stenosed vessels.

Influence of smoking, hypertension, and sex on the phenotypic expression of familial intracranial aneurysms in siblings.

OBJECTIVE: To investigate the effects of smoking, hypertension, and sex on the phenotypic expression of familial intracranial aneurysms (FIAs). METHODS: We retrospectively reviewed the case records of 806 consecutive patients undergoing aneurysm surgery at our institution (1986-1995) and discovered 24 families with at least two affected siblings. Prevalence rates for the smoking, hypertension, and sex risk factors in these nuclear families were compared with those of patients with sporadic intracranial aneurysms (SIAs) and population-based control patients. RESULTS: Affected family members with FIAs exhibited prevalence rates of smoking and hypertension (74% and 43%, respectively) that tended to be higher than those of population-based control patients (52% [P < 0.005] and 36% [P = not significant (NS)], respectively) and comparable to those of patients with SIAs (64% [P = NS] and 40% [P = NS], respectively). A positive association existed between FIA formation and female sex but was somewhat less strong than that observed in the SIAs (59% FIAs, 71% SIAs, 50% control patients). In addition, the prevalence rates of smoking, hypertension, and female sex were higher in affected family members with FIAs than in their unaffected siblings (58% [P < 0.05], 28% [P = 0.06], and 39% [P < 0.05], respectively). Individuals in families with expressed FIAs who had high aneurysmal penetrance had a greater tendency to be smokers, hypertensive, and female (74%, 59%, and 55%, respectively) than did their low-penetrance counterparts (61% [P = 0.1], 27% [P < 0.05], and 45% [P = NS], respectively). CONCLUSION: Together these data suggest that hypertension, smoking, and female sex increase the likelihood that a member of a family with an expressed FIA will have an aneurysm. These observations may prove helpful in guiding the use of screening studies and encouraging education about the potential risks of continued tobacco use and untreated hypertension in this patient cohort.

Assessment of response function in two PET scanners with and without interplane septa.

The authors have assessed the response function both experimentally and theoretically for two commercial tomographs: CTI 931/08-12 and CTI 953B with and without interplane septa. Monte Carlo simulations were undertaken using the GEANT package from CERN. Spatial resolution (tomographic and axial) was calculated for line sources at various positions in the field of view. Sensitivity and scatter fraction (SF) were calculated for various source geometries as a function of energy discrimination. A very realistic response function in positron emission tomography (PET) is obtained by Monte Carlo methods, using global parameters to account for unsimulated phenomena such as scintillation light transport inside a detector block and its sharing among the various phototubes. Minor discrepancies remain for sensitivity and SF at high energy thresholds and may probably be explained by introducing the observed dispersion in the energy response for the various crystals within a detector block.

Noise equivalent count measurements in a neuro-PET scanner with retractable septa.

The noise-equivalent count-rate (NEC) performance of a neuro-positron emission tomography (PET) scanner has been determined with and without interplane septa on uniform cylindrical phantoms of differing radii and in human studies to assess the optimum count rate conditions that realize the maximum gain. In the brain, the effective gain in NEC performance for three-dimensions (3-D) ranges from >5 at low count rates to approximately 3.3 at 200 kcps (equivalent to 37 kcps in 2-D). The gains of the 3-D method assessed by this analysis are significant, and are shown to be highly dependent on count rate and object dimensions.

Fully three-dimensional reconstruction for a PET camera with retractable septa.

A fully 3-D reconstruction algorithm has been developed to reconstruct data from a 16 ring PET camera (a Siemens/CTI 953B) with automatically retractable septa. The tomograph is able to acquire coincidences between any pair of detector rings and septa retraction increases the total system count rate by a factor of 7.8 (including scatter) and 4.7 (scatter subtracted) for a uniform, 20 cm diameter cylinder. The reconstruction algorithm is based on 3-D filtered backprojection, expressed in a form suitable for the multi-angle sinogram data. Sinograms which are not measured due to the truncated cylindrical geometry of the tomograph, but which are required for a spatially invariant response function, are obtained by forward projection. After filtering, the complete set of sinograms is backprojected into a 3-D volume of 128x128x31 voxels using a voxel-driven procedure. The algorithm has been validated with simulation, and tested with both phantom and clinical data from the 953B.

Effect of size and composition of the body on absolute measurement of calcium in vivo.

The effect of size and composition of the body on the measurement of total calcium in absolute units by neutron activation analysis is described. The neutron beam, produced from a cyclotron, was of mean energy 7.5 MeV. Counting of the activities induced in a patient was carried out with a multidetector whole body counter. Calibration of the system was achieved by using two phantoms of different sizes containing known quantities of calcium. The dimensions of various phantom sections were varied to determine the effect on efficiency of activation, an approximately linear relationship with body thickness being found. The influence of body habitus on counting efficiency was assessed by counting different patients who had been given known quantities of 42K. The effects of (a) the non-uniform distribution of calcium and (b) the variation in density of different tissues on both activation and counting efficiency are discussed. It is estimated that the 68% confidence limits on the measurement of 49Ca count rate per unit neutron fluence is +/- 3.0% and on the measurement of calcium in grams +/- 8.2%.

Diagnostic features of Alzheimer's disease extracted from PET sinograms.

Texture analysis of positron emission tomography (PET) images of the brain is a very difficult task, due to the poor signal to noise ratio. As a consequence, very few techniques can be implemented successfully. We use a new global analysis technique known as the Trace transform triple features. This technique can be applied directly to the raw sinograms to distinguish patients with Alzheimer's disease (AD) from normal volunteers. FDG-PET images of 18 AD and 10 normal controls obtained from the same CTI ECAT-953 scanner were used in this study. The Trace transform triple feature technique was used to extract features that were invariant to scaling, translation and rotation, referred to as invariant features, as well as features that were sensitive to rotation but invariant to scaling and translation, referred to as sensitive features in this study. The features were used to classify the groups using discriminant function analysis. Cross-validation tests using stepwise discriminant function analysis showed that combining both sensitive and invariant features produced the best results, when compared with the clinical diagnosis. Selecting the five best features produces an overall accuracy of 93% with sensitivity of 94% and specificity of 90%. This is comparable with the classification accuracy achieved by Kippenhan et al (1992), using regional metabolic activity.

Calculation of single detector efficiencies and extension of the normalization sinogram in PET.

A fast iterative method is presented for calculating single detector efficiencies for positron emission tomographs. These efficiencies can be used to extend the normalization scan to areas outside that covered by the normalization source. The root mean square (rms) error of the calculated single detector efficiencies decreases exponentially with the number of iterations. Thirty iterations per normalization image are sufficient and take about 1 s on a SUN Classic. The geometry factors are composed of factors which only depend on the distance from the centre of the field-of-view (FOV) and of factors which show a more complex pattern over the normalization sinogram. The geometry factors are specific to each scanner. On the ECAT 931 scanner the complex part of the geometry factors showed a diamond shaped pattern (caused by the varying sensitivity of single detectors in a detector block with varying angle of incidence) and S-shaped curves (representing attenuation caused by supporting rods for the ring source). The coefficient of variation of the diamond-shaped pattern was 4% for detectors farthest from the centre of the FOV. Extensions of the normalization scan may, therefore, contain a relative rms error of about 4% if the applied geometry factors only take the distance from the centre of the FOV into account.

Measurement of total body nitrogen and oxygen by irradiation with cyclotron neutrons and 'delayed' gamma ray counting.

Measurement of total body nitrogen is assuming increasing importance in the nutritional evaluation of seriously ill patients. Nitrogen has been previously measured either by counting (i) the annihilation radiation from 13N immediately after neutron irradiation with 14 MeV neutrons or (ii) the 'prompt' gamma rays from thermal neutron capture by 14N during irradiation with 14 MeV neutrons or with those produced by isotopic sources or a cyclotron. The present work describes studies into the feasibility of measuring 13N produced by irradiation with a neutron beam from the MRC Cyclotron. A complication of this method is that 13N is also produced in a reaction with 16O. Direct measurement of oxygen by use of the reactions 16O(n, p)16N or 16O(n, 2n)15O enables this interference to be estimated. The former reaction is possible with both 14 meV and cyclotron-produced neutrons but the 7.1 s half-life of 16N requires detectors to be placed in or very close to the irradiation site. In our particular circumstances this is not possible but the more energetic cyclotron neutron spectrum allows the production of 15O which has a half-life of 2.05 min and can be measured in a remote whole-body counter. A disadvantage with the cyclotron beam, in comparison with 14 MeV neutrons, is that a higher dose is required for similar accuracy. A reproducibility of about 4% is obtained with a dose equivalent of 0.01 Sv.

Three-dimensional performance of a small-diameter positron emission tomograph.

Recently, the initial 2D physical characterization of a small-diameter positron emission tomograph, designed specifically for scanning of small laboratory animals, was reported. The physical characteristics of the tomograph operating in 3D mode have now been measured and compared to those obtained in 2D mode. In 3D, the transaxial resolution was measured as 2.4 +/- 0.1 mm full width at half maximum (FWHM) and 6.7 +/- 1.1 mm full width at tenth maximum (FWTM) at the centre of the transaxial field of view (FOV). These values degraded to 4.5 +/- 0.3 mm (tangential) and 6.6 +/- 0.3 mm (radial) FWHM and 10.6 +/- 1.6 mm (tangential) and 11.2 +/- 2.1 mm (radial) FWTM, respectively, at a distance of 40 mm from the centre of the transaxial FOV. The axial resolution was measured as 4.6 +/- 0.1 mm FWHM and 15.0 +/- 0.5 mm FWTM at the centre of the transaxial FOV, increasing to 5.0 +/- 0.1 mm FWHM and 18.8 +/- 3.7 mm FWTM at a radial distance of 40 mm from the centre of the transaxial FOV. These resolutions are similar to those obtained for the tomograph operating in 2D mode. The sensitivity of the tomograph operating in 3D was 4.31 x 10(4) counts s-1 MBq-1 at 250-850 keV compared to 0.995 x 10(4) counts s-1 MBQ-1 in 2D at the same energy thresholds. In this energy window the noise equivalent count rate peaked at 4.1 x 10(4) counts s-1, compared to 1.03 x 10(4) counts s-1 in 2D. A scatter fraction of 30.2% at 250-850 keV was measured for a 18F line source centered in a 60 mm diameter water filled phantom in 3D, compared to 31.0% in 2D for the same scanning geometry and energy thresholds. A comparison was made between 2D and 3D kinetic analyses for a group of five anaesthetized rats scanned using [11C] SCH 23390, a marker of dopamine D1 receptors. The integrity of the results was maintained between 2D and 3D data sets, though in 3D there was a significant reduction in the standard error of the fitted parameter. The results demonstrate that, with regard to sensitivity, there are significant gains in the physical performance of this tomograph when operating in 3D compared to 2D mode and that the quantification of PET studies of small animals using the 3D data reflects this.