| | Susceptibility-Weighted Imaging and Proton Magnetic Resonance Spectroscopy in Assessment of Outcome After Pediatric Traumatic Brain InjuryAbstract Ashwal S, Babikian T, Gardner-Nichols J, Freier M-C, Tong KA, Holshouser BA. Susceptibility-weighted imaging and proton magnetic resonance spectroscopy in assessment of outcome after pediatric traumatic brain injury. ObjectiveTo assess the role of magnetic resonance imaging, specifically magnetic resonance spectroscopy (MRS) and susceptibility-weighted imaging (SWI), in the evaluation of children with traumatic brain injury (TBI). Data SourcesLiterature review and data from our recently published clinical studies. Study SelectionChildren with pediatric TBI who underwent SWI. SWI is a 3-dimensional high-resolution magnetic resonance imaging technique that is more sensitive in detecting hemorrhagic lesions seen with diffuse axonal injury (DAI) than conventional imaging. MRS acquires metabolite information that reflects neuronal integrity and function from multiple brain regions and offers early prognostic information regarding outcome. Data ExtractionLiterature review. Data SynthesisLiterature review and review of recently published data from our institution. ConclusionsThe data suggest that more sensitive imaging techniques that provide early evidence of injury and that are better predictors of outcome are needed to identify children at risk for such deficits. Specifically, the number and volume of hemorrhagic DAI lesions as well as changes in spectral metabolites such as reduced N-acetylaspartate or elevations in choline-related compounds correlate with neurologic disability and impairments of global intelligence, memory, and attention. TRAUMATIC BRAIN INJURY (TBI) is among the most frequent pediatric neurologic disorders and is a significant contributor to childhood morbidity and mortality.1 Evaluation of brain injury in children is complicated by the limited predictive power of injury severity indicators such as the Glasgow Coma Scale (GCS) score, duration of impaired consciousness and of posttraumatic amnesia, presence of nonreactive pupils, and brain imaging techniques. When combined, clinical indicators more accurately predict neurologic outcome but still only correctly classify about 80% of gross neurologic outcomes in children. Although a significant proportion of children with TBI regain ambulatory and self-care skills, many have long-term neuropsychologic and behavioral deficits, including impaired intellectual abilities (verbal, nonverbal), academic performance, attention, memory, learning, problem solving, processing speed, language, visual perception, and visual motor skills.1, 2, 3, 4, 5, 6, 7 Despite the dramatic impact of computed tomography (CT) and magnetic resonance imaging (MRI) on the early surgical and medical evaluation of children with TBI, they have not proven sufficiently sensitive or specific in determining long-term neurologic and neuropsychologic outcomes. Even with improved ability to detect diffuse axonal injury (DAI) using traditional MRI methods, it remains difficult to diagnose, and often clinical suspicions of DAI are inconsistent with neuroimaging results. Recently susceptibility-weighted imaging (SWI) and magnetic resonance spectroscopic imaging (MRSI) have emerged as 2 new promising MRI techniques that have immense potential to more accurately assess the severity and regional distribution of injury after TBI. They appear particularly useful for the assessment of DAI, which is responsible for a wide range of motor and cognitive impairments. These techniques, which can be implemented on standard clinical MRI scanners, greatly improve the ability to more accurately assess injury after TBI in children, a population that frequently is overlooked for study but in whom permanent injury is associated with a lifetime of hardship and disability. In this review we describe these 2 methods and their usefulness in assessing long-term neurologic and neuropsychologic outcome. Susceptibility-weighted imaging  Although MRI is often superior to CT for the detection of small hemorrhages, the MRI appearance of hemorrhage is variable and dependent on multiple factors, including the state of oxygenation of deoxyhemoglobin, integrity of the red blood cell, field strength of the MRI scanner, receiver bandwith, type of sequence, and degree of T1 or T2 weighting.8 Most blood products are paramagnetic, making it possible to exploit magnetic susceptibility effects in order to make hemorrhages more visible on sequences that accentuate signal loss from rapid spin dephasing. In the acute and early subacute phases, these effects largely occur from deoxyhemoglobin and methemoglobin. As spins are affected by different fields, they precess at different rates and cause signal loss in T2*-weighted (ie, gradient echo) images. Sensitivity to the magnetic susceptibility effects of hemorrhage increase as the method progresses from fast spin echo to routine spin echo to gradient echo techniques, from T1 to T2 to T2* weighting, from short to long echo times, and from lower to higher field strengths. Until recently, conventional 2-dimensional gradient recalled echo (GRE) T2*-weighted images have been most sensitive for detecting hemorrhage. SWI is a modified 3-dimensional GRE T2*-weighted technique with unique postprocessing that allows improved detection of paramagnetic hemorrhagic blood products based on their magnetic susceptibility effects related to phase dispersion caused by the presence of extravascular deoxyhemoglobin and methemoglobin.9 Hemorrhagic and nonhemorrhagic shearing lesions associated with DAI occur in up to 40% of children with TBI.10 Also, more subtle microscopic injury, which may not be visible with currently available neuroimaging techniques, may contribute to significant functional impairments.11 The pathology of DAI is characterized histologically by widespread damage to axons in several brain regions including the brainstem, parasagittal white matter, “hallmark” hemorrhagic lesions in the corpus callosum, and the gray-white matter junctions of the cerebral cortex.12 Immunohistochemistry has shown that the extent and distribution of axonal injury resulting from TBI appears similar in children and adults.13 Considering the widespread consequences of DAI, its detection is important for the evaluation, treatment, and prognosis of TBI patients, particularly in those with moderate injuries where damage and/or repair may currently go unrecognized. MRI has provided substantial improvement in the ability to detect hemorrhagic and nonhemorrhagic lesions.14, 15, 16 Several early small case series17, 18, 19, 20 of DAI in children found varying outcomes but were unable to correlate the extent of early injury with prognosis. Newer imaging methods have further improved detection of susceptibility-related effects of hemorrhagic shearing injury.21, 22, 23, 24 Scheid et al24 found that T2*-weighted GRE sequences detected significantly more lesions than conventional T1- or T2-weighted sequences, in adult TBI patients, using high-field (3.0T) MRI. Although there was a correlation between the total amount of small hemorrhages and GCS, they found no correlation with patient outcomes measured by the Glasgow Outcome Scale (GOS) score. More recently, this group conducted neuropsychologic testing in a group of adult patients with DAI microbleeds detected on T2*-weighted GRE sequences at 3.0T and showed that memory and executive function were most often impaired. However, no significant correlations were found between the amount of microbleeds and cognitive performance.25 Grados et al22 used a spoiled gradient echo T1-weighted MRI sequence to show that depth and number of lesions predicted outcome in children, although correlations were stronger with discharge outcomes compared with 1-year outcomes. Levin et al16 showed a correlation between depth of brain lesions (using T1, T2, and GRE sequences) and outcomes measured by GOS as well as the Vineland Adaptive Behavior Scale−Revised. In all these studies, MRI was acquired late after injury. In recent studies, SWI has been shown to be very useful in detecting hemorrhagic lesions associated with DAI.7 This sequence, which can be performed on conventional scanners, was originally designed for magnetic resonance venography using the paramagnetic property of intravascular deoxyhemoglobin26 but has since been found to be useful for detection of hemorrhage. Early work with this technique has been primarily performed at 1.5-T field strength and is likely superior to conventional T2*-weighted gradient echo imaging at 3.0-T field strength, although direct comparison has not been performed. In addition, SWI is now available on 3.0-T scanners, which would further improve the sensitivity to susceptibility effects from hemorrhage. Very high field MRI scanners (eg, 7.0T) have shown marked sensitivity to susceptibility effects but are not clinically practical. An initial report using SWI at 1.5T, which studied 7 children with TBI (age, 14±4y; SWI done 5±3d postinjury), showed that the number of hemorrhagic DAI lesions seen on SWI was 6 times greater than on conventional T2*-weighted 2-dimensional GRE imaging and that the volume of hemorrhage was approximately 2-fold greater.7 A comparison of SWI with 2-dimensional GRE in a TBI patient is seen in figure 1. SWI and Neurologic Status In an expanded SWI study, 40 children and adolescents with mild to severe TBI and DAI (mean age, 12y; SWI, 7±4d postinjury) were examined.21 The number and volume of hemorrhagic lesions were compared with long-term neurologic outcome measured by the Pediatric Cerebral Performance Category Scale (PCPCS) score, a 6-point outcome scoring system modified from the GOS that quantifies the overall functional neurologic morbidity and cognitive impairment of infants and children.27 The study found that children with lower GCS scores (≤8) or prolonged coma (>4d) had a significantly greater average number and volume of hemorrhagic lesions (fig 2). In addition, children with normal outcomes or mild neurologic disability as determined by the PCPCS score at 6 to 12 months after injury had significantly fewer number and volume of hemorrhagic DAI lesions than those who were moderately or severely disabled or in a vegetative state (Fig 2, Fig 3). Differences in regional DAI injury were also evaluated. Over 90% of patients had lesions in parieto-temporal-occipital gray matter, parieto-temporal-occipital white matter, or frontal white matter. Four regions were less commonly affected (ie, <65% of patients), including the thalamus, brainstem, cerebellum, and basal ganglia. Twelve (30%) of the 40 patients had lesions in all 9 of the brain regions examined. Forty-two percent of these patients had poor outcomes. There were 14 patients who had lesions in 6 or fewer regions, and all had good outcomes at 6 to 12 months. Only patients with involvement of 7 or more regions had poor outcomes. Figure 4 shows examples of hemorrhagic DAI lesions detected in TBI patients, which illustrate that this high-resolution SWI algorithm allows for better detection of lesions, even in brain regions close to the skull and regions such as the brainstem that are not normally accessible with conventional MRI. SWI and Neuropsychologic Outcome Because SWI is much more sensitive than conventional T2*-weighted gradient echo sequences in detecting hemorrhagic DAI, it may provide more accurate prognostic information regarding long-term neuropsychologic outcome. In a study of 18 children and adolescents with mild to severe TBI (all accidental trauma), MRI, including SWI and spectroscopy, was conducted 6±4 days postinjury.28 Significant correlations between SWI hemorrhagic lesion number and lesion volume with cognitive measures were noted. These included measures of intelligence, executive skills, attention, visuoperceptual skills, language, verbal and nonverbal memory, motor functioning, and academic achievement (spelling, reading, mathematics). Lesion volume alone explained over 32% of the variability in cognitive scores. As shown in table 1, strong correlations were seen between specific brain regions and neuropsychologic testing. This was particularly true in the subcortical pooled region where moderate to strong associations from the basal ganglia and thalamic regions dominated in all neuropsychologic domains.28, 29 Magnetic resonance spectroscopy Magnetic resonance spectroscopy (MRS), now available on most clinical MRI scanners, is a noninvasive neuroimaging tool that allows in vivo analysis of neurochemicals and their metabolites in humans.30 MRI uses the strong signals from proton nuclei of water and their spatial location to reconstruct anatomic images. In contrast, 1H-MRS focuses on protons located on neurochemicals other than water that are present in much lower concentrations within tissues, and thus it necessitates the use of water suppression techniques and reduced spatial resolution compared with imaging in order to measure them. 1H-MRS is the most widely used application of in vivo MRS in humans and will be discussed in this review, but other atoms that are used include 31P, 13C, 14N, 19F, and 23Na. Single voxel spectroscopy (SVS) allows acquisition of a single spectrum from 1 volume element (voxel) at approximately 8mL or more, whereas 2- or 3-dimensional MRSI, also called chemical shift imaging (CSI), allows simultaneous acquisition of multiple spectra from smaller adjacent voxels through multiple sections of the brain in order to create a regional distribution of neurochemical alterations of metabolites. Metabolites in 1H-MRS Several key brain metabolites are measured with 1H-MRS using both short (ie, echo time [TE], 20−40ms) and long (ie, TE=135−270ms) echo time SVS and MRSI techniques. Each metabolite resonates at a particular frequency and thus shows up on a magnetic resonance (MR) spectrum at a known chemical shift (measured in ppm). N-acetylaspartate (NAA) (2.01ppm), an amino acid synthesized in mitochondria, is a neuronal and axonal marker that decreases with neuronal loss or dysfunction. Total creatine (3.0ppm) composed of phosphocreatine and its precursor creatine is a marker for intact brain energy metabolism. Total choline (3.02ppm), primarily consisting of phosphoryl and glycerophosphoryl choline, is a marker for membrane synthesis or repair, inflammation, or demyelination. Increased choline after TBI may be an indication of cell membrane shearing injury or astrocytosis.31 Lactate (1.33ppm) accumulates as a result of anaerobic glycolysis and, in the context of TBI, may be a response to release of glutamate.32 Short echo time acquisitions allow for measurement of additional metabolites not seen with long echo time acquisitions because the metabolites have short T2 relaxation times. Specifically, glutamate and immediately formed glutamine (2.1−2.4ppm) are excitatory amino acids released after brain injury that play a major role in neuronal death.33 Myoinositol (3.56ppm), an organic osmolyte in astrocytes, increases after glial proliferation.34 After acquisition, spectral processing identifies key metabolites according to their chemical shift resonance, measures the area under each peak corresponding to their concentration, and reports the findings as peak area metabolite ratios, such as NAA/creatine and choline/creatine. It was thought that creatine is maintained at a constant level in the brain, and thus creatine was used in early studies as an internal standard. Although it is known that creatine levels can change in certain conditions, ratios continue to be useful for reporting and comparing serial measurements or data between institutions using similar acquisition techniques. Methods have been developed to quantitate metabolite levels in MRS and are used routinely. These methods often use water as an internal reference or phantoms containing known metabolite concentrations to quantify peak areas and report absolute or relative metabolite concentrations rather than ratios.35, 36 Metabolite levels vary by region37 and change with development,38 requiring the use of normal age-matched reference data for interpreting MR spectra in children. Quantitative assessments of the normal distribution of metabolite levels in neonates report spectral differences among anatomic locations and between premature and term groups.39 Metabolite changes associated with brain maturation and myelination continue rapidly through the first year of life39, 40 and continue to a lesser degree through adolescence.41, 42 Figure 5 illustrates these age related changes, with rapidly increasing levels of NAA and creatine from birth through the first year of life and decreasing levels of choline and myoinositol levels in normal developing gray matter. Single-Voxel Studies and Neurologic and Neuropsychologic Outcome Single-voxel MRS has shown potential for providing early prognostic information regarding clinical outcome in pediatric patients with head injury.40, 43, 44 Early studies in gray matter of neonates, infants, and children with central nervous system injury have shown strong correlations between reduced NAA/creatine and NAA/choline and increased choline/creatine and lactate with the severity of injury and duration of coma and with poor neurologic outcome (severe disability, vegetative state, death) as measured by the PCPCS score assessed 6 to 12 months after injury.40 Several MRS studies have shown its utility in detecting DAI. Elevated choline detected in white matter may be a breakdown product after shearing of myelin and cellular membranes, and reduced NAA likely results from neuronal or axonal injury.45 Studies specifically looking at the splenium of the corpus callosum in patients with brain injury showed decreased NAA.46, 47 MRS has been used to study children with accidental and nonaccidental trauma.43 Short-echo SVS from normal-appearing occipital gray matter and parietal white matter measured at a mean of 5±3 days postinjury in 26 infants (1−18mo) and 8±6 days postinjury in 28 children (≥18mo) found lower NAA/creatine or NAA/choline and higher choline/creatine in poor outcome patients. Lactate was present in 91% of infants and 80% of children with poor outcomes; none of the good-outcome patients had lactate. Using a logistic regression model, clinical variables alone predicted outcome in 77% of infants and 86% of children, whereas lactate presence alone predicted outcome in 96% of infants and children. These findings showed that MRS acquired early after injury was more accurate than clinical variables in predicting outcome. The strong correlation between lactate and outcome was primarily in infants who had nonaccidental trauma rather than accidental trauma. Of great interest was that spectra from brain areas that did not appear visibly injured showed altered metabolite ratios that correlated with injury. Quantitation of short echo time MRS using a time-domain fitting routine (linear combination model)36 was performed in 1 study in children and facilitated the measurement of myoinositol and glutamate levels along with NAA, creatine, choline, and lactate. In this study of 38 children (MRS at 7±4d postinjury), myoinositol levels from occipital gray matter were increased in children with TBI.48 Patients with poor outcomes had higher myoinositol levels compared with patients with good outcomes. It was postulated that increased myoinositol in TBI patients with poor long-term neurologic outcome was due to astrogliosis or to a disturbance in osmotic function. In addition, glutamate from occipital gray matter was significantly increased in children with TBI compared with controls, but there was no difference between children with good compared with poor outcomes.49 This finding was attributed to the delay from the time of injury to imaging in severe TBI patients who required additional days of medical stabilization before transport to the scanner compared with children with mild-to-moderate injury. According to the literature, glutamate levels peak early after injury and fall rapidly.49 Therefore, glutamate differences may have been present between outcome groups if the timing of the measurements were controlled. Few studies have directly compared MRS metabolite data with neuropsychologic outcomes. However, 1 group studied adult TBI patients with moderate-to-severe TBI and correlated metabolite levels from normal-appearing parieto-occipital gray and white matter with neurologic outcome50 and neuropsychologic performance.51, 52 They found that gray matter NAA changes measured 1.5 months after injury predicted the GOS score and that NAA changes in gray and white matter positively correlated with composite neuropsychologic function. This study not only showed that NAA changes correlate with neuropsychologic performance but also that NAA decreases are still detectable up to 1.5 months postinjury. Another study evaluating neuropsychologic function in children with TBI who had MRS (SVS in gray and white matter as described above) studied 22 children who were 1 week to 14 years of age at the time of TBI.44 Neuropsychologic testing done 1 to 7 years after injury included measures of intellectual functioning, memory, linguistic abilities, planning, attention, visuospatial processing, and sensorimotor abilities. The ratios—NAA/choline, choline/creatine, and lactate—accurately classified between 73% and 100% of the infants and children as functioning above or below the average range for the intellectual and neuropsychologic outcome measures. Another investigator conducted single voxel proton MRS in the chronic phase after severe TBI (1−12y postinjury) in 15 pediatric patients (10−16y at the time of testing). Compared with 15 healthy age- and sex-matched controls, the TBI group had significantly lower NAA and choline in the right frontal lobe with generally poor performance on neuropsychologic tests, including measures of intelligence, memory, and executive functions. A correlation between reaction times and metabolites (NAA or NAA/creatine) was also evident.53 Both acute and late MRS studies following pediatric head injury support the strong potential for using MRS to provide accurate estimates of long-term neuropsychologic function after TBI in infants and children. Mutivoxel MRSI Studies and Neurologic and Neuropsychologic Outcome A few studies have evaluated TBI using MRSI in adults or children. Macmillan et al54 studied normal and abnormal areas of brain as seen on T2-weighted images in adult patients after TBI with and without subarachnoid hemorrhage and found low NAA levels in both areas compared with controls. Reduction of NAA in visibly injured brain is most likely caused by the primary impact, whereas reduction of NAA in normal-appearing brain may reflect DAI and Wallerian degeneration, the anterograde or retrograde loss of axons that connect to regions of focal damage.34 Another study55 showed a uniform global reduction of NAA in head-injured patients that returned to normal in patients who made a good recovery. A recent study56 using volumetric proton spectroscopic imaging (3-dimensional MRSI) in 14 adults with mild TBI found significant reductions in NAA/creatine and NAA/choline and increases in choline/creatine compared with controls in regions of brain appearing normal on conventional MR images, further illustrating the high sensitivity of noninvasive MRS for evaluating diffuse brain injury.56 A recent study using 2-dimensional MRSI in normal-appearing occipital and frontal regions of school-aged children, 6 weeks to 3 years after TBI, showed that NAA/choline ratios were lower in TBI patients than in control subjects, but no group differences were present for choline or creatine.57 Another study, using a combination of 2-dimensional MRSI and SWI in children with TBI, found that NAA-derived ratios averaged from all voxels through the level of the corpus callosum were significantly decreased in children with poor neurologic outcomes and that voxels containing hemorrhage as seen on SWI had lower NAA/creatine ratios than voxels that did not.58 In this study, 2-dimensional MRSI in 40 pediatric TBI patients was acquired in a transverse plane through the level of the corpus callosum within 1 to 16 days postinjury. T2-weighted, fluid-attentuated inversion recovery, and SWI were used to identify voxels as normal appearing or with nonhemorrhagic or hemorrhagic injury. Neurologic outcome was evaluated at 6 to 12 months after injury using the PCPCS score. A significant decrease in NAA/creatine and increase in choline/creatine (evidence of DAI) was observed in normal-appearing and visibly injured (hemorrhagic) brain compared with controls. NAA/creatine was decreased more in normal-appearing brain for poor outcome patients compared with patients with good outcomes or controls. Ratios from normal-appearing brain predicted outcome with 85% accuracy compared with 67% using ratios from visibly injured brain. Shown in figure 6 are examples of SWI and MRSI in a patient from this study (see legend for detailed description). These figures show the exquisite localization that can be accomplished with these techniques, the superior sensitivity of SWI in detecting hemorrhagic DAI lesions, and that a spectrum from normal-appearing brain has decreased NAA, which indicates neuronal injury or dysfunction. The neuropsychologic profile of this patient approximately 2 years postinjury (age, 17y) was indicative of generally weaker verbal skills (including verbal memory) compared with nonverbal, slow visuomotor processing speed, and impaired motor coordination. These findings emphasize the additional information detected by MRSI that is not seen by currently used conventional neuroimaging or SWI. MRSI voxel data from TBI patients in the above study were analyzed quantitatively. In patients with good outcomes, an average of 8.2% of the voxels contained hemorrhagic lesions and 1.6% contained nonhemorrhagic DAI lesions. This is compared with patients with poor outcomes, in whom a larger percentage of voxels contained hemorrhagic lesions (27.6%) compared with nonhemorrhagic lesions (2.2%). The percentage of voxels from normal-appearing brain in which NAA/creatine ratios were below 2 standard deviations of normal for age in each patient was determined. Figure 7 is a plot of these percentages grouped by neurologic outcome assessed at 6 to 12 months after injury. Approximately 60% of voxels from normal-appearing brain taken at the level of the corpus callosum in children who have normal or mildly abnormal long-term neurologic outcomes have decreased NAA/creatine ratios early after injury. The percentage of voxels from normal-appearing brain with abnormal metabolite ratios increases with increasing severity of outcome. This shows that proton MRSI is extremely sensitive for detecting neuronal injury in brain that appears normal on neuroimaging. This is also an excellent demonstration of the diffuse nature of TBI and may help to explain why global neuropsychologic deficits are often seen in patients with normal imaging findings. As mentioned by Hunter et al,57 the MRS literature lacks information concerning the long-term effects of pediatric TBI on alterations in neurometabolites in relation to neurobehavioral, intellectual, or neuropsychologic functioning. In their study, 2-dimensional CSI with voxels of interest in the anterior and posterior regions of the left and right frontoparietal areas was conducted. Imaging was completed in the subacute phase (weeks to 3−4mo) to the chronic phase (3y) postinjury in 7 mild-to-severe pediatric head injury patients. Intellectual function, expressive language, and arithmetic skills were measured within 2 weeks of imaging. All 3 measures were lower in the TBI group than the control group. Decreased NAA levels were moderately related to intellectual functioning and arithmetic. Associations between choline and creatine with cognitive scores were less consistent and weaker. The authors concluded that NAA levels remain low during recovery after TBI and correlates with cognitive functions. In our own study of 20 children with TBI (all accidental trauma), MRS was conducted during the acute phase after injury (6±4d postinjury). It was found that NAA measurements and its derived ratios correlated positively and moderately to strongly with intellectual and neuropsychologic scores 1 to 4 years postinjury.29 Global NAA/creatine ratios from MRSI alone explained over 40% of the variance in cognitive scores. Analyses comparing the global NAA/creatine mean ratios from MRSI data with results of neuropsychologic testing of 9 cognitive domains indicated strong (r>.50) and statistically significant (P<.05) correlations between regional reductions in NAA and specific neuropsychologic functions. Reduced NAA was strongly correlated in all brain regions with full scale intelligence quotient and visuoperceptual skills, and almost all regions with attention and language functioning. The MRSI results from these studies were encouraging because they showed the potential value of using spectroscopy to assess risk for neuropsychologic impairments. Conclusions An important issue that has emerged is the time after injury when neuroimaging, including these newer techniques, should be acquired. A single time point has not emerged from the literature as the optimal time after injury that MR neurometabolites should be measured. Rather, the time point should be optimized for the metabolite that one is most interested in studying. Serial studies in rodent and human cerebrospinal fluid have shown that glutamate levels are affected early after injury and can return to normal levels within days, whereas rodent and swine studies49 have shown that NAA decreases also occur within days after diffuse TBI, quickly recover only in tissue less injured, and remain decreased in more severely injured brain. Our own studies in children and adults using MRS suggest that the optimum time to measure glutamate is early (within days after injury) whereas NAA should be measured after 7 days.49, 59 Future studies will need to carefully address this issue to determine the optimal time to do MRS after pediatric TBI to maximize data acquisition required to predict long-term outcome. For this purpose, it cannot be assumed that data from adult studies accurately apply to children, because it is very likely that the processes of posttraumatic neurodegeneration, recovery, and plasticity are developmentally sensitive. 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a Department of Pediatrics, Division of Child Neurology, Section of Neuroradiology, Loma Linda University School of Medicine, Loma Linda, CA b Department of Clinical Psychology, Section of Neuroradiology, Loma Linda University School of Medicine, Loma Linda, CA c Department of Radiology, Section of Neuroradiology, Loma Linda University School of Medicine, Loma Linda, CA  Correspondence to Stephen Ashwal, MD, Dept of Pediatrics, Loma Linda University School of Medicine, 11175 Campus St, Loma Linda, CA 92350
No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated. PII: S0003-9993(06)01280-9 doi:10.1016/j.apmr.2006.07.275 © 2006 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved. | |
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