A Bainbridge

Cerebral Magnetic Resonance Biomarkers in Neonatal Encephalopathy: A Meta-analysis

OBJECTIVE: Accurate prediction of neurodevelopmental outcome in neonatal encephalopathy (NE) is important for clinical management and to evaluate neuroprotective therapies. We undertook a meta-analysis of the prognostic accuracy of cerebral magnetic resonance (MR) biomarkers in infants with neonatal encephalopathy. METHODS: We reviewed all studies that compared an MR biomarker performed during the neonatal period with neurodevelopmental outcome at ≥1 year. We followed standard methods recommended by the Cochrane Diagnostic Accuracy Method group and used a random-effects model for meta-analysis. Summary receiver operating characteristic curves and forest plots of each MR biomarker were calculated. χ2 tests examined heterogeneity. RESULTS: Thirty-two studies (860 infants with NE) were included in the meta-analysis. For predicting adverse outcome, conventional MRI during the neonatal period (days 1–30) had a pooled sensitivity of 91% (95% confidence interval [CI]: 87%–94%) and specificity of 51% (95% CI: 45%–58%). Late MRI (days 8–30) had higher sensitivity but lower specificity than early MRI (days 1–7). Proton MR spectroscopy deep gray matter lactate/N-acetyl aspartate (Lac/NAA) peak-area ratio (days 1–30) had 82% overall pooled sensitivity (95% CI: 74%–89%) and 95% specificity (95% CI: 88%–99%). On common study analysis, Lac/NAA had better diagnostic accuracy than conventional MRI performed at any time during neonatal period. The discriminatory powers of the posterior limb of internal capsule sign and brain-water apparent diffusion coefficient were poor. CONCLUSIONS: Deep gray matter Lac/NAA is the most accurate quantitative MR biomarker within the neonatal period for prediction of neurodevelopmental outcome after NE. Lac/NAA may be useful in early clinical management decisions and counseling parents and as a surrogate end point in clinical trials that evaluate novel neuroprotective therapies.

Mural Inflammation in Crohn Disease: Location-Matched Histologic Validation of MR Imaging Features

PURPOSE To validate proposed magnetic resonance (MR) imaging features of Crohn disease activity against a histopathologic reference. MATERIALS AND METHODS Ethical permission was given by the University College London hospital ethics committee, and informed written consent was obtained from all participants. Preoperative MR imaging was performed in 18 consecutive patients with Crohn disease undergoing elective small-bowel resection. The Harvey-Bradshaw index, the C-reactive protein level, and disease chronicity were recorded. The resected bowel was retrospectively identified at preoperative MR imaging, and wall thickness, mural and lymph node/cerebrospinal fluid (CSF) signal intensity ratios on T2-weighted fat-saturated images, gadolinium-based contrast material uptake, enhancement pattern, and mesenteric signal intensity on T2-weighted fat-saturated images were recorded. Precise histologic matching was achieved by imaging the ex vivo surgical specimens. Histopathologic grading of acute inflammation with the acute inflammatory score (AIS) (on the basis of mucosal ulceration, edema, and quantity and depth of neutrophilic infiltration) and the degree of fibrostenosis was performed at each site, and results were compared with MR imaging features. Data were analyzed by using linear regression with robust standard errors of the estimate. RESULTS AIS was positively correlated with mural thickness and mural/CSF signal intensity ratio on T2-weighted fat-saturated images (P < .001 and P = .003, respectively) but not with mural enhancement at 30 and 70 seconds (P = .50 and P = .73, respectively). AIS was higher with layered mural enhancement (P < .001), a pattern also commonly associated with coexisting fibrostenosis (75%). Mural/CSF signal intensity ratio on T2-weighted fat-saturated images was higher in histologically edematous bowel than in nonedematous bowel (P = .04). There was no correlation between any lymph node characteristic and AIS. CONCLUSION Increasing mural thickness, high mural signal intensity on T2-weighted fat-saturated images, and a layered pattern of enhancement reflect histologic features of acute small-bowel inflammation in Crohn disease.

Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model

Despite treatment with therapeutic hypothermia, almost 50% of infants with neonatal encephalopathy still have adverse outcomes. Additional treatments are required to maximize neuroprotection. Melatonin is a naturally occurring hormone involved in physiological processes that also has neuroprotective actions against hypoxic-ischaemic brain injury in animal models. The objective of this study was to assess neuroprotective effects of combining melatonin with therapeutic hypothermia after transient hypoxia-ischaemia in a piglet model of perinatal asphyxia using clinically relevant magnetic resonance spectroscopy biomarkers supported by immunohistochemistry. After a quantified global hypoxic-ischaemic insult, 17 newborn piglets were randomized to the following: (i) therapeutic hypothermia (33.5°C from 2 to 26 h after resuscitation, n = 8) and (ii) therapeutic hypothermia plus intravenous melatonin (5 mg/kg/h over 6 h started at 10 min after resuscitation and repeated at 24 h, n = 9). Cortical white matter and deep grey matter voxel proton and whole brain (31)P magnetic resonance spectroscopy were acquired before and during hypoxia-ischaemia, at 24 and 48 h after resuscitation. There was no difference in baseline variables, insult severity or any physiological or biochemical measure, including mean arterial blood pressure and inotrope use during the 48 h after hypoxia-ischaemia. Plasma levels of melatonin were 10 000 times higher in the hypothermia plus melatonin than hypothermia alone group. Melatonin-augmented hypothermia significantly reduced the hypoxic-ischaemic-induced increase in the area under the curve for proton magnetic resonance spectroscopy lactate/N-acetyl aspartate and lactate/total creatine ratios in the deep grey matter. Melatonin-augmented hypothermia increased levels of whole brain (31)P magnetic resonance spectroscopy nucleotide triphosphate/exchangeable phosphate pool. Correlating with improved cerebral energy metabolism, TUNEL-positive nuclei were reduced in the hypothermia plus melatonin group compared with hypothermia alone in the thalamus, internal capsule, putamen and caudate, and there was reduced cleaved caspase 3 in the thalamus. Although total numbers of microglia were not decreased in grey or white matter, expression of the prototypical cytotoxic microglial activation marker CD86 was decreased in the cortex at 48 h after hypoxia-ischaemia. The safety and improved neuroprotection with a combination of melatonin with cooling support phase II clinical trials in infants with moderate and severe neonatal encephalopathy.

Mural Crohn Disease: Correlation of Dynamic Contrast-enhanced MR Imaging Findings with Angiogenesis and Inflammation at Histologic Examination—Pilot Study

PURPOSE To determine mural perfusion dynamics in Crohn disease by using dynamic contrast material-enhanced magnetic resonance (MR) imaging and to correlate these with histopathologic markers of inflammation and angiogenesis. MATERIALS AND METHODS Ethical permission was given by the University College London Hospital ethics committee, and informed consent was obtained from all participants. Eleven consecutive patients with Crohn disease (eight female patients, three men; mean age, 39.5 years; range, 16.4-66.6 years) undergoing elective small-bowel resection were recruited between July 2006 and December 2007. Harvey-Bradshaw index, C-reactive protein (CRP) level, and disease chronicity were recorded. Preoperatively, dynamic contrast-enhanced MR imaging was performed through the section of bowel destined for resection, and slope of enhancement, time to maximum enhancement, enhancement ratio, the volume transfer coefficient K(trans), and the extracellular volume fraction v(e) were calculated for the affected segment. Ex vivo surgical specimens were imaged to facilitate imaging-pathologic correlation. Histopathologic sampling of the specimen was performed through the imaged tissue, and microvascular density (MVD) was determined, together with acute and chronic inflammation scores. Correlations between clinical, MR imaging, and histopathologic data were made by using the Kendall rank correlation and linear regression. RESULTS Disease chronicity was positively correlated with enhancement ratio (correlation coefficient, 0.82; P = .002). Slope of enhancement demonstrated a significant negative correlation with MVD (correlation coefficient, -0.86; P < .001). There was a negative correlation between CRP level and slope of enhancement (correlation coefficient, -0.77; P = .006). Neither acute nor chronic inflammation score correlated with any other parameter. CONCLUSION Certain MR imaging-derived mural hemodynamic parameters correlate with disease chronicity and angiogenesis in Crohn disease, but not with histologic and clinical markers of inflammation. Data support the working hypothesis that microvessel permeability increases with disease chronicity and that tissue MVD is actually inversely related to mural blood flow.

Pediatric and Adolescent Lymphoma: Comparison of Whole-Body STIR Half-Fourier RARE MR Imaging with an Enhanced PET/CT Reference for Initial Staging

PURPOSE To compare the diagnostic performance of rapid whole-body anatomic magnetic resonance (MR) staging of pediatric and adolescent lymphoma to an enhanced positron emission tomographic (PET)/computed tomographic (CT) reference standard. MATERIALS AND METHODS Ethical permission was given by the University College London Hospital ethics committee, and informed written consent was obtained from all participants and/or parents or guardians. Thirty-one subjects (age range, 7.3-18.0 years; 18 male, 11 female) with histologically proved lymphoma were prospectively recruited. Pretreatment staging was performed with whole-body short inversion time inversion-recovery (STIR) half-Fourier rapid acquisition with relaxation enhancement (RARE) MR imaging, fluorine 18 fluorodeoxyglucose PET/CT, and contrast agent-enhanced chest CT. Twenty-six subjects had posttreatment PET/CT and compromised our final cohort. Eleven nodal and 11 extranodal sites per patient were assessed on MR imaging by two radiologists in consensus, with a nodal short-axis threshold of >1 cm and predefined extranodal positivity criteria. The same sites were independantly evaluated by two nuclear medicine physicians on PET/CT images. Disease positivity was defined as a maximum standardized uptake value >2.5 or nodal size >1 cm. An unblinded expert panel reevaluated the imaging findings, removing perceptual errors, and derived an enhanced PET/CT reference standard (taking into account chest CT and 3-month follow-up imaging) against which the reported and intrinsic performance of MR imaging was assessed by using the kappa statistic. RESULTS There was very good agreement between MR imaging and the enhanced PET/CT reference standard for nodal and extranodal staging (kappa = 0.96 and 0.86, respectively) which improved following elimination of perceptual errors (kappa = 0.97 and 0.91, respectively). The sensitivity and specificity of MR imaging (following removal of perceptual error) were 98% and 99%, respectively, for nodal disease and 91% and 99%, respectively, for extranodal disease. CONCLUSION Whole-body STIR half-Fourier RARE MR imaging of pediatric and adolescent lymphoma can accurately depict nodal and extranodal disease and may provide an alternative nonionizing imaging method for anatomic disease assessment at initial staging.

Xenon augmented hypothermia reduces early lactate/N-acetylaspartate and cell death in perinatal asphyxia

Additional treatments for therapeutic hypothermia are required to maximize neuroprotection for perinatal asphyxial encephalopathy. We assessed neuroprotective effects of combining inhaled xenon with therapeutic hypothermia after transient cerebral hypoxia–ischemia in a piglet model of perinatal asphyxia using magnetic resonance spectroscopy (MRS) biomarkers supported by immunohistochemistry.

Depth of delayed cooling alters neuroprotection pattern after hypoxia-ischemia

Hypothermia after perinatal hypoxia‐ischemia (HI) is neuroprotective; the precise brain temperature that provides optimal protection is unknown. To assess the pattern of brain injury with 3 different rectal temperatures, we randomized 42 newborn piglets: (Group i) sham‐normothermia (38.5–39°C); (Group ii) sham‐33°C; (Group iii) HI‐normothermia; (Group iv) HI‐35°C; and (Group v) HI‐33°C. Groups iii through v were subjected to transient HI insult. Groups ii, iv, and v were cooled to their target rectal temperatures between 2 and 26 hours after resuscitation. Experiments were terminated at 48 hours. Compared with normothermia, hypothermia at 35°C led to 25 and 39% increases in neuronal viability in cortical gray matter (GM) and deep GM, respectively (both p < 0.05); hypothermia at 33°C resulted in a 55% increase in neuronal viability in cortical GM (p < 0.01) but no significant increase in neuronal viability in deep GM. Comparing hypothermia at 35 and 33°C, 35°C resulted in more viable neurons in deep GM, whereas 33°C resulted in more viable neurons in cortical GM (both p < 0.05). These results suggest that optimal neuroprotection by delayed hypothermia may occur at different temperatures in the cortical and deep GM. To obtain maximum benefit, you may need to design patient‐specific hypothermia protocols by combining systemic and selective cooling. Ann Neurol 2005;58:75–87

Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe): a proof-of-concept, open-label, randomised controlled trial

Summary Background Moderate cooling after birth asphyxia is associated with substantial reductions in death and disability, but additional therapies might provide further benefit. We assessed whether the addition of xenon gas, a promising novel therapy, after the initiation of hypothermia for birth asphyxia would result in further improvement. Methods Total Body hypothermia plus Xenon (TOBY-Xe) was a proof-of-concept, randomised, open-label, parallel-group trial done at four intensive-care neonatal units in the UK. Eligible infants were 36–43 weeks of gestational age, had signs of moderate to severe encephalopathy and moderately or severely abnormal background activity for at least 30 min or seizures as shown by amplitude-integrated EEG (aEEG), and had one of the following: Apgar score of 5 or less 10 min after birth, continued need for resuscitation 10 min after birth, or acidosis within 1 h of birth. Participants were allocated in a 1:1 ratio by use of a secure web-based computer-generated randomisation sequence within 12 h of birth to cooling to a rectal temperature of 33·5°C for 72 h (standard treatment) or to cooling in combination with 30% inhaled xenon for 24 h started immediately after randomisation. The primary outcomes were reduction in lactate to N-acetyl aspartate ratio in the thalamus and in preserved fractional anisotropy in the posterior limb of the internal capsule, measured with magnetic resonance spectroscopy and MRI, respectively, within 15 days of birth. The investigator assessing these outcomes was masked to allocation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00934700, and with ISRCTN, as ISRCTN08886155. Findings The study was done from Jan 31, 2012, to Sept 30, 2014. We enrolled 92 infants, 46 of whom were randomly assigned to cooling only and 46 to xenon plus cooling. 37 infants in the cooling only group and 41 in the cooling plus xenon group underwent magnetic resonance assessments and were included in the analysis of the primary outcomes. We noted no significant differences in lactate to N-acetyl aspartate ratio in the thalamus (geometric mean ratio 1·09, 95% CI 0·90 to 1·32) or fractional anisotropy (mean difference −0·01, 95% CI −0·03 to 0·02) in the posterior limb of the internal capsule between the two groups. Nine infants died in the cooling group and 11 in the xenon group. Two adverse events were reported in the xenon group: subcutaneous fat necrosis and transient desaturation during the MRI. No serious adverse events were recorded. Interpretation Administration of xenon within the delayed timeframe used in this trial is feasible and apparently safe, but is unlikely to enhance the neuroprotective effect of cooling after birth asphyxia. Funding UK Medical Research Council.

Brain Cell Death Is Reduced With Cooling by 3.5°C to 5°C but Increased With Cooling by 8.5°C in a Piglet Asphyxia Model

Background and Purpose— In infants with moderate to severe neonatal encephalopathy, whole-body cooling at 33°C to 34°C for 72 hours is standard care with a number needed to treat to prevent a adverse outcome of 6 to 7. The precise brain temperature providing optimal neuroprotection is unknown. Methods— After a quantified global cerebral hypoxic-ischemic insult, 28 piglets aged <24 hours were randomized (each group, n=7) to (1) normothermia (38.5°C throughout) or whole-body cooling 2 to 26 hours after insult to (2) 35°C, (3) 33.5°C, or (4) 30°C. At 48 hours after hypoxia-ischemia, delayed cell death (terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling and cleaved caspase 3) and microglial ramification (ionized calcium-binding adapter molecule 1) were evaluated. Results— At 48 hours after hypoxia-ischemia, substantial cerebral injury was found in the normothermia and 30°C hypothermia groups. However, with 35°C and 33.5°C cooling, a clear reduction in delayed cell death and microglial activation was observed in most brain regions (P<0.05), with no differences between 35°C and 33.5°C cooling groups. A protective pattern was observed, with U-shaped temperature dependence in delayed cell death in periventricular white matter, caudate nucleus, putamen, hippocampus, and thalamus. A microglial activation pattern was also seen, with inverted U-shaped temperature dependence in periventricular white matter, caudate nucleus, internal capsule, and hippocampus (all P<0.05). Conclusions— Cooling to 35°C (an absolute drop of 3.5°C as in therapeutic hypothermia protocols) or to 33.5°C provided protection in most brain regions after a cerebral hypoxic-ischemic insult in the newborn piglet. Although the relatively wide therapeutic range of a 3.5°C to 5°C drop in temperature reassured, overcooling (an 8.5°C drop) was clearly detrimental in some brain regions.

Brain mitochondrial oxidative metabolism during and after cerebral hypoxia-ischemia studied by simultaneous phosphorus magnetic-resonance and broadband near-infrared spectroscopy☆

Background Multimodal measurements combining broadband near-infrared spectroscopy (NIRS) and phosphorus magnetic resonance spectroscopy (31P MRS) assessed associations between changes in the oxidation state of cerebral mitochondrial cytochrome-c-oxidase (Δ[oxCCO]) and 31P metabolite peak-area ratios during and after transient cerebral hypoxia–ischemia (HI) in the newborn piglet. Methods Twenty-four piglets (aged < 24 h) underwent transient HI (inspired oxygen fraction 9% and bilateral carotid artery occlusion for ~ 20 min). Whole-brain 31P MRS and NIRS data were acquired every minute. Inorganic phosphate (Pi)/epp, phosphocreatine (PCr)/epp, and total nucleotide triphosphate (NTP)/epp were measured by 31P MRS and were plotted against Δ[oxCCO] during HI and recovery (epp = exchangeable phosphate pool = Pi + PCr + 2γ-NTP + β-NTP). Results During HI Δ[oxCCO], PCr/epp and NTP/epp declined and Pi/epp increased. Significant correlations were seen between 31P ratios and Δ[oxCCO]; during HI a threshold point was identified where the relationship between Δ[oxCCO] and both NTP/epp and Pi/epp changed significantly. Outcome at 48 h related to recovery of Δ[oxCCO] and 31P ratios 1 h post-HI (survived: 1-h NTP/epp 0.22 ± 0.02, Δ[oxCCO] − 0.29 ± 0.50 μM; died: 1-h NTP/epp 0.10 ± 0.04, Δ[oxCCO] − 2.41 ± 1.48 μM). Conclusions Both lowered Δ[oxCCO] and NTP/epp 1 h post-HI indicated mitochondrial impairment. Animals dying before 48 h had slower recovery of both Δ[oxCCO] and 31P ratios by 1 h after HI.