Therapeutic Hypothermia for Neonatal Encephalopathy Results in Improved Microstructure and Metabolism in the Deep Gray Nuclei

Department of Neurology, Radiology and Biomedical Imaging, Epidemiology and Biostatistics, and Pediatrics, University of California at San Francisco, San Francisco, California.
American Journal of Neuroradiology (Impact Factor: 3.59). 05/2012; 33(11). DOI: 10.3174/ajnr.A3117
Source: PubMed


BACKGROUND AND PURPOSE:Therapeutic hypothermia has reduced morbidity and mortality and is associated with a lower burden of lesions on conventional imaging in NE. However, its effects on brain microstructure and metabolism have not been fully characterized. We hypothesized that therapeutic hypothermia improves measures of brain microstructure and metabolism.MATERIALS AND METHODS:Forty-one neonates with moderate/severe NE (29 treated with hypothermia, 12 nontreated) and 12 healthy neonates underwent MR imaging, DTI, and (1)H-MR spectroscopy. MR imaging scans were scored by the predominant pattern of brain injury: normal, watershed, and BG/thalamus. ADC, FA, Lac:NAA, and NAA:Cho values from bilateral BG and thalamus ROIs were averaged. T test and linear regression analysis were used to determine the association between hypothermia and MR imaging quantitative measures.RESULTS:Conventional MR imaging findings were normal in 41% of treated neonates; all nontreated neonates had brain injury. Values of MR imaging metrics were closer to normal in treated neonates compared with nontreated neonates: ADC was 63% higher in the BG and 116% higher in the thalamus (both P < .05), and Lac:NAA was 76% lower (P = .04) in the BG. Treated neonates with normal MR imaging findings had normal (1)H-MR spectroscopy metabolites, and ADC was higher by 35% in the thalamus (P = .03) compared with healthy neonates.CONCLUSIONS:Therapeutic hypothermia may reduce disturbances of brain metabolism and preserve its microstructure in the setting of NE, possibly by minimizing cytotoxic edema and cell death. Long-term follow-up studies are required to determine whether early post-treatment DTI and (1)H-MR spectroscopy will be useful biomarkers of treatment response.

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Available from: Hannah C Glass, Feb 20, 2015
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    • "Injury versus no injury: * í µí± < 0.05, * * í µí± < 0.005, and * * * or not developing brain injury in 40 asphyxiated newborns treated with hypothermia on MRI scanned around day 7 of life (range: days 5–12 of life, eight newborns developed brain injury). Bonifacio et al. [28] showed that ADC values were higher and closer to normal in 29 asphyxiated newborns treated with hypothermia scanned around day 5 of life (range: days 4–6 of life, 12 newborns developed brain injury), compared with the asphyxiated newborns, who were not treated [28]; however, the newborns treated with hypothermia were usually imaged one day later compared with the not treated newborns, and " pseudonormalization " may have accounted for some of these reduced diffusion abnormalities [28]. Thakur et al. [31] concluded that ADC values are more likely to be abnormal when they are performed closer to the cessation of hypothermic treatment between days 4 and 8 of life; however, they did not perform any imaging before day 4 of life in their study of 44 asphyxiated newborns treated with hypothermia scanned around day 7 of life (range: days 4–17 of life, 14 newborns developed later brain injury) [31]. "
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    ABSTRACT: The objective of this study was to assess the evolution of diffusion-weighted imaging (DWI) and diffusion-tensor imaging (DTI) over the first month of life in asphyxiated newborns treated with hypothermia and to compare it with that of healthy newborns. Asphyxiated newborns treated with hypothermia were enrolled prospectively; and the presence and extent of brain injury were scored on each MRI. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values were measured in the basal ganglia, in the white matter and in the cortical grey matter. Sixty-one asphyxiated newborns treated with hypothermia had a total of 126 ADC and FA maps. Asphyxiated newborns developing brain injury eventually had significantly decreased ADC values on days 2-3 of life and decreased FA values around day 10 and 1 month of life compared with those not developing brain injury. Despite hypothermia treatment, asphyxiated newborns may develop brain injury that still can be detected with advanced neuroimaging techniques such as DWI and DTI as early as days 2-3 of life. A study of ADC and FA values over time may aid in the understanding of how brain injury develops in these newborns despite hypothermia treatment.
    Full-text · Article · Jul 2015
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    • "For MRS metabolites, developmental changes are well described: NAA increases , while mI decreases with increasing GA at scan. But gestational age at birth and post-natal age may also affect the outcome of a scan done at term age [33] [34] [35] [36]. Gestational age at birth may be important if subsequent development of the brain region depends heavily on the stage at which the infant was exposed to the extrauterine environment, or if brain injury occurs near the time of birth [37]. "
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    ABSTRACT: Purpose: To determine specific motor skills in premature infants, match those that correlate with standards tests of motor performance, and MRS measures of abnormal brain biochemistry. Methods: Prospective cohort study of preterm infants (n=22). Infant motor assessments were completed at term and 12 weeks corrected gestational age (CGA) using the Test of Infant Motor Performance (TIMP) and Bayley Scales of Infant and Toddler Development-III at 12 months CGA. Infants (n=12) received MRS scans at term CGA. Rasch analysis and MRS findings investigated TIMP items well targeted to high and low risk infants. Results: A 10 item subset of motor skill items correlated strongly with full 42-item TIMP at term and 12 week testing (r> 0.90, p< 0.001 for both), and with Bayley gross motor scores. MRS metabolites in basal ganglia correlated significantly with both TIMP and 10 item motor tests at term, while frontal white matter metabolites correlated with TIMP and 10 item tests at 12 weeks and Bayley motor scores. Conclusion: A short motor skill assessment may be representative of a longer standardized test and relate to brain metabolic function in key areas for motor movement and development. Validation of a shortened assessment may improve early identification of high-risk preterm infants.
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    ABSTRACT: Therapeutic hypothermia is standard of care for infants with hypoxic ischemic encephalopathy. Murine models of hypoxic-ischemic injury exist; however, a well-established mouse model of therapeutic hypothermia following hypoxic-ischemic injury is lacking. The goal of this study was to develop a full-term-equivalent murine model of therapeutic hypothermia after hypoxia-ischemia and examine magnetic resonance imaging, behavior, and histology in a region and sex specific manner. Hypoxic-ischemic injury was induced at postnatal day 10 in C57BL6 mice using a modified Vannucci model. Mice were randomized to control, hypothermia (31˚C for 4h), or normothermia (36˚C) following hypoxic-ischemic injury and stratified by sex. T2-weighted magnetic resonance imaging was obtained at postnatal day 18 and 30 and regional and total cerebral and cerebellar volumes measured. Behavioral assessments were performed on postnatal day 14, 21, and 28. On postnatal day 18, normothermic mice had smaller cerebral volumes (p < 0.001 vs. controls and p = 0.009 vs. hypothermia), while at postnatal day 30 both injured groups had smaller volumes than controls. When stratified by sex, only normothermia treated male mice had smaller cerebral volumes (p = 0.001 vs. control; p = 0.008 vs. hypothermia) at postnatal day 18, which persisted at postnatal day 30 (p = 0.001 vs. control). Female mice had similar cerebral volumes between groups at both day 18 and 30. Cerebellar volumes of hypothermia treated male mice differed from control at day 18, but not at 30. Four hours of therapeutic hypothermia in this murine hypoxic-ischemic injury model provides sustained neuroprotection in the cerebrum of male mice. Due to variable degree of injury in female mice, response to therapeutic hypothermia is difficult to discern. Deficits in female behavior tests are not fully explained by imaging measures and likely represent injury not detectable by volume measurements alone.
    Full-text · Article · Mar 2015 · PLoS ONE
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