Proton magnetic resonance spectroscopy improves outcome prediction in perinatal CNS insults.

OBJECTIVE: Prediction of neurologic outcome is difficult in neonates with acute nervous system injury. Previous studies using proton magnetic resonance spectroscopy ((1)H-MRS) have been used to predict short-term neurologic outcome in neonates with a variety of neurologic insults. We were interested in determining the effectiveness of combining clinical evaluation and spectroscopy obtained at the time of injury in predicting neurologic outcome at 24 months. STUDY DESIGN: We studied 33 neonates with acute central nervous system injury, 5.8+/-3.7 days of injury, owing to hypoxic-ischemic encephalopathy. Neonates were assessed using clinical variables (initial arterial pH, initial blood glucose, Sarnat score, electroencephalography) and spectroscopy (NAA/Cho, NAA/Cre, Cho/Cre, and lactate). Neonates were divided into two outcome groups: good/moderate and poor. Differences between the groups were assessed using chi(2) and t-test analyses. We analyzed the best predictors of outcome using discriminant analysis and calculated sensitivity, specificity, positive, and negative predictive values for each variable independently and in combination. RESULTS: There were significant differences between the good/moderate and poor outcome for the Sarnat score, EEG, lactate, and NAA/Cho. Spectroscopy combined with clinical variables improved sensitivity, but not specificity for predicting outcome. The presence of lactate had the best individual predictive value. Combination of the clinical with the MRS variables had the highest predictive value. CONCLUSION: Proton magnetic resonance spectroscopy done early after injury improves the ability to predict neurologic outcome at 24 months of age.     

Chronic suppression of insulin by diazoxide alters the activities of key enzymes regulating hepatic gluconeogenesis in Zucker rats

OBJECTIVES: Chronic attenuation of hyperinsulinemia by diazoxide (DZ), an inhibitor of glucose-mediated insulin secretion, improved insulin sensitivity and glucose tolerance and caused down-regulation of lipid metabolizing enzymes in adipose tissue and decreased the rate of weight gain in mildly hyperglycemic obese Zucker rats. Since the liver plays a central role in glucose homeostasis, we studied the effect of chronic insulin suppression on key insulin-sensitive enzymes regulating hepatic gluconeogenesis. METHODS: DZ (150 mg/kg per day) or vehicle (control) was administered to 7-week-old female obese and lean Zucker rats for a period of 4 weeks. RESULTS: DZ-treated animals showed lower fasting plasma insulin levels (P<0.001) than their controls. Plasma glucose levels were lower in DZ obese rats than in controls (P<0.001), without a significant change in DZ lean animals. DZ had no effect on glucose transporter 2 protein expression in either strain. DZ treatment resulted in lower hepatic glucokinase (P<0.001) and glucose-6-phosphatase (P<0.0001) and phosphoenolpyruvate carboxykinase (PEPCK) activities only in obese rats compared with controls (P<0.001). However, DZ-treated lean rats demonstrated higher PEPCK activity than controls (P<0.002). DZ-treated animals demonstrated enhanced hepatic glucose-6-phosphate content (P<0.01), glycogen synthase activity (P<0.0001) and glycogen content (P<0.02) compared with their controls despite increased hepatic glycogen phosphorylase a activity in these animals (P<0.02). CONCLUSIONS: Chronic suppression of hyperinsulinemia in obese Zucker rats by DZ decreased the activities of key enzymes regulating hepatic gluconeogenesis, implying that attenuation of the hyperinsulinemic state by DZ may be therapeutically beneficial.     

Susceptibility weighted imaging: neuropsychologic outcome and pediatric head injury

Traumatic brain injury is among the most frequent pediatric neurologic disorders in the United States, affecting multiple aspects of neuropsychologic functioning. This study assessed the efficacy of susceptibility weighted imaging as a predictor of long-term neuropsychologic functioning after pediatric brain injury compared with magnetic resonance spectroscopic imaging. Susceptibility weighted imaging is a relatively new method that is considered superior to traditional magnetic resonance imaging sequences for detecting hemorrhagic diffuse axonal injury. In this study, imaging and spectroscopy were acquired 6 +/- 4 days after injury. Measures of neuropsychologic functioning were administered to 18 children and adolescents 1-4 years post injury. Negative correlations between lesion number and volume with neuropsychologic functioning were demonstrated. Lesion volume explained over 32% of the variance in cognitive performance, explaining at least an additional 20% beyond injury severity and age at injury alone and 19% beyond magnetic resonance spectroscopic metabolite variables. Exploratory analyses resulted in notable trends, with lesions in deeper brain regions more strongly associated with poorer neuropsychologic performance. Improved detection of the extent of diffuse axonal injury following a brain injury will allow for a better understanding of its association with long-term outcome, which in turn can improve prognostic efficacy for effective treatment planning.     

MR spectroscopy study of dichloroacetate treatment after ischemic stroke

In a double-blind, placebo-controlled study, we used 1H MR spectroscopy to assess the effect of a single infusion of sodium dichloroacetate on lesion lactate 1 to 5 days after ischemic stroke. Apparent trends toward a reduction in lactate/N-acetyl compound ratios were seen at the higher drug doses employed, and in patients treated in the first 2 days following infarction. Use of spectroscopic measures as endpoints is feasible in acute stroke clinical trials.     

Proton MR spectroscopic imaging depicts diffuse axonal injury in children with traumatic brain injury

BACKGROUND AND PURPOSE: Diffuse axonal injury (DAI) after traumatic brain injury (TBI) is important in patient assessment and prognosis, yet they are underestimated with conventional imaging techniques. We used MR spectroscopic imaging (MRSI) to detect DAI and determine whether metabolite ratios are accurate in predicting long-term outcomes and to examine regional differences in injury between children with TBI and control subjects. METHODS: Forty children with TBI underwent transverse proton MRSI through the level of the corpus callosum within 1-16 days after injury. T2-weighted, fluid-attenuated inversion recovery, and susceptibility-weighted MR imaging was used to identify voxels as normal-appearing or as nonhemorrhagic or hemorrhagic injury. Neurologic outcome was evaluated at 6-12 months after injury. Metabolite ratios for total (all voxels), normal-appearing, and hemorrhagic brain were compared and used in a logistic regression model to predict long-term outcome. Total and regional metabolite ratios were compared with control data. RESULTS: A significant decrease in N-acetylaspartate (NAA)/creatine (Cr) and increase in choline (Cho)/Cr (evidence of DAI) was observed in normal-appearing (P < .05) and visibly injured (hemorrhagic) brain (P < .001) compared with controls. In normal-appearing brain NAA/Cr decreased more in patients with poor outcomes (1.32 +/- 0.54) than in those with good outcomes (1.61 +/- 0.50, P = .01) or control subjects (1.86 +/- 0.1, P = .00). In visibly injured brains, ratios were similarly altered in all patients. In predicting outcomes, ratios from normal-appearing and visibly-injured brain were 85% and 67% accurate, respectively. CONCLUSION: MRSI can depict injury in brain that appears normal on imaging and is useful for predicting long-term outcomes.     

Proton MR spectroscopy detected glutamate/glutamine is increased in children with traumatic brain injury

Adults with traumatic brain injury (TBI) have been shown by invasive methods to have increased levels of the excitatory neurotransmitter glutamate. It is unclear whether glutamate release contributes to primary or secondary injury and whether its protracted elevation is predictive of a poor outcome. Preliminary studies at our institution in adults found that early increases in magnetic resonance spectroscopy (MRS)-detected glutamate/glutamine (Glx) were associated with poor outcomes. We therefore studied 38 children (mean age, 11 years; range, 1.6-17 years) who had TBI with quantitative short-echo time (STEAM, TE = 20 msec) proton MRS, a mean of 7 +/- 4 (range, 1-17) days after injury in order to determine if their occipital or parietal Glx levels correlated with the severity of injury or outcome. Occipital Glx was significantly increased in children with TBI compared to controls (13.5 +/- 2.4 vs. 10.7 +/- 1.8; p = 0.002), but there was no difference between children with good compared to poor outcomes as determined by the Pediatric Cerebral Performance Category Scale score at 6-12 months after injury. We also did not find a correlation between the amount of Glx and the initial Glasgow Coma Scale score, duration of coma, nor with changes in spectral metabolites, including N-acetyl aspartate, choline, and myoinositol. In part, this may have occurred because, in this study, most patients with poor outcomes were studied later than patients with good outcomes, potentially beyond the time frame for peak elevation of Glx after injury. Additional early and late studies of patients with varying degrees of injury are required to assess the importance to the pathophysiology of TBI of this excitatory neurotransmitter.     

Predicting neuropsychologic outcome after traumatic brain injury in children

The ability to predict long-term neurologic and neuropsychologic outcomes in 22 children, ages 1 week to 14 years at the time of traumatic brain injury, was investigated using proton magnetic resonance spectroscopy acquired post injury and compared with standardized neurologic, intellectual, and neuropsychologic testing done 1-7 years later. Clinical indicators of acute injury severity including age at injury, electroencephalography, spectroscopy metabolite ratio variables (N-acetyl aspartate/choline, choline/creatine) and lactate presence accurately classified children as functioning above or below the average range for most intellectual and neuropsychologic outcome measures. Combined clinical and spectroscopy variables accounted for approximately 50% of the variance in cognitive and neuropsychologic outcome confirming the validity of their predictive use. Of the injury severity indictors, presence of lactate is a particularly important prognostic marker of poor long-term intellectual and neuropsychologic functioning. Our findings indicate the potential for providing accurate estimates of long-term intellectual and neuropsychologic function after traumatic brain injury in infants and children using proton magnetic resonance spectroscopy in combination with clinical variables.     

Prospective longitudinal proton magnetic resonance spectroscopic imaging in adult traumatic brain injury

PURPOSE: To investigate whether longitudinal magnetic resonance proton spectroscopic imaging (MRSI) demonstrates regional metabolite abnormalities after traumatic brain injury (TBI) that predict long-term neurologic outcome. MATERIALS AND METHODS: Two-dimensional-MRSI (point resolved spectroscopy sequence [PRESS]; TR/TE = 3000/144 msec; 10 mm) was acquired prospectively in 42 adults with severe TBI through the level of the corpus callosum 7 +/- 4 days after injury. Measurements were repeated in 31 patients six to 12 months after injury. Regional and pooled (all regions combined) mean ratios were compared with control values and then used to predict long-term (six- to -12-month) neurologic outcome (good vs. poor) using a logistic regression model. RESULTS: Initial pooled mean N-acetylaspartate (NAA) ratios were lower (P < 0.01) and choline (Cho)/creatine (Cr) ratios higher (P < 0.01) in all TBI patients compared to controls. Ratios from the corpus callosum region were affected most and predicted long-term dichotomized outcome with 83% accuracy. When repeated at six to 12 months after injury, pooled mean NAA/Cr remained lower (P = 0.03) and Cho/Cr remained higher (P = 0.01) in patients with poor outcomes. CONCLUSION: The NAA/Cr ratio from the corpus callosum was most useful for outcome prediction. Chronic alterations of metabolite ratios are likely due to neuronal loss and glial proliferation long after injury.     

Magnetic resonance spectroscopy and electroencephalography in baclofen coma

This report describes a 14-year-old female who presented with coma and seizures. Continuous electroencephalographic monitoring revealed suppression and semiperiodic sharp waves. Magnetic resonance spectroscopy performed 1 day after admission suggested a good outcome despite her clinical examination and electroencephalogram. She was subsequently found to have elevated serum baclofen levels after an intentional overdose. At the time of her discharge from the pediatric intensive care unit, she manifested no neurologic deficits, and on telephone follow-up 2 years after the ingestion the patient had no complaints of any cognitive problems or neurologic dysfunction.