Chapter 1



Quantification of ante-mortem hypoxic ischemic brain injury by post-mortem cerebral magnetic resonance imaging in neonatal encephalopathy Short Title: Post-mortem MRI in Neonatal EncephalopathyKey words: Neonatal encephalopathy, post-mortem, magnetic resonance imagingAbbreviations:SUND: Sudden Unexplained Neonatal DeathNE: Neonatal EncephalopathyPLIC: Posterior Limb of the Internal CapsuleDESTIR: Double-Echo Short Tau Inversion Recovery FLASH: Fast Low Angle Shot CISS: Constructive Interference in the Steady StateDWI: Diffusion-Weighted ImagingADC: Apparent Diffusion Coefficient SIR: Signal Intensity RatioROI: Region of InterestABSTRACTPost-mortem (PM) magnetic resonance imaging (MRI) is increasingly used as an alternative to conventional autopsy in babies dying from neonatal encephalopathy. However, the confounding effect of post-mortem changes on the detection of ante-mortem ischemic injury is unclear. We examined whether quantitative MR measurements can accurately distinguish ante-mortem ischemic brain injury from artifacts using post-mortem MRI.METHODS We compared PM brain MRI (1.5 T Siemens, Avanto) in 7 infants who died with neonatal encephalopathy (NE) of presumed hypoxic-ischemic origin with 7 newborn infants who had sudden unexplained neonatal death (SUND controls) without evidence of hypoxic-ischemic brain injury at autopsy. We measured apparent diffusion coefficients (ADCs), T1-weighted signal intensity ratios (SIRs) compared to vitreous humor and T2 relaxation times from 19 predefined brain areas typically involved in neonatal encephalopathy.RESULTSThere were no differences in mean ADC values, SIRs on T1-weighted images or T2 relaxation times in any of the 19 predefined brain areas between NE and SUND infants. All MRI images showed loss of cortical gray-white matter differentiation, loss of the normal high signal intensity (SI) in posterior limb of internal capsule on T1-weighted images, and high white matter SI on T2-weighted images. CONCLUSION Normal post-mortem changes may be easily mistaken for ante-mortem ischemic injury, and current PM MRI quantitative assessment cannot reliably distinguish these . These findings may have important implications for appropriate interpretation on PM imaging findings, especially in medico-legal practice. INTRODUCTIONDespite therapeutic hypothermia, a quarter of infants with neonatal encephalopathy still die in the UK and other high-income countries. Post-mortem (PM) examination in such cases is important to establish the etiology and timing of events, exclude underlying congenital defects that might recur, and to identify additional cerebral pathologies, for example intracranial bleedsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TcXVpZXI8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 1. Furthermore, birth asphyxia related brain injuries are of medico-legal significance and one of the most common reasons for obstetric litigation worldwide, and hence accurate identification of the cause of death and underlying pathology is important ADDIN EN.CITE <EndNote><Cite><Author>Kurinczuk JJ</Author><Year>2010</Year><RecNum>709</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>709</rec-number><foreign-keys><key app="EN" db-id="wxwerdx0kps5r0e5zwever58r5rx9xrz9fz9">709</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kurinczuk JJ, </author><author>White-Koning M, </author><author>Badawi N</author></authors></contributors><titles><title>Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy.</title><secondary-title>Early Hum Dev</secondary-title></titles><periodical><full-title>Early Hum Dev</full-title></periodical><pages>329-38</pages><volume>86</volume><number>6</number><dates><year>2010</year></dates><urls></urls></record></Cite></EndNote>2. However, consented neonatal autopsy rates are currently less than 20% in the UK and other developed countries ADDIN EN.CITE <EndNote><Cite><Year>2009</Year><RecNum>54</RecNum><DisplayText><style face="superscript">3</style></DisplayText><record><rec-number>54</rec-number><foreign-keys><key app="EN" db-id="fapxrv5zn905sxezxelperrservz5x25rrxd">54</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors></contributors><titles><title>Confidential Enquiry into Maternal and Child Health: Perinatal Mortality</title><secondary-title>.uk/getattachment/.../Perinatal-Mortality-2007.aspx (accessed 25.1.2010)</secondary-title></titles><periodical><full-title>.uk/getattachment/.../Perinatal-Mortality-2007.aspx (accessed 25.1.2010)</full-title></periodical><pages>London</pages><dates><year>2009</year></dates><urls></urls></record></Cite></EndNote>3. Therefore, there is increasing interest in using PM magnetic resonance imaging (MRI) for diagnosis of neuropathological lesionsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmVlemU8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 4-6, including hypoxic ischemic brain injury ADDIN EN.CITE <EndNote><Cite><Author>Nicholl</Author><Year>2007</Year><RecNum>138</RecNum><DisplayText><style face="superscript">7</style></DisplayText><record><rec-number>138</rec-number><foreign-keys><key app="EN" db-id="varp2e5agaw2phezrf2xzdekee5twfzzat9f">138</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nicholl, R. M.</author><author>Balasubramaniam, V. P.</author><author>Urquhart, D. S.</author><author>Sellathurai, N.</author><author>Rutherford, M. A. Comment</author></authors></contributors><auth-address>Neonatal Unit, Northwick Park Hospital, North West London Hospitals NHS Trust, London, UK. richard.nicholl@nwlh.nhs.uk</auth-address><titles><title>Postmortem brain MRI with selective tissue biopsy as an adjunct to autopsy following neonatal encephalopathy</title><secondary-title>Eur J Paediatr Neurol</secondary-title></titles><periodical><full-title>Eur J Paediatr Neurol</full-title></periodical><pages>167-74</pages><volume>11</volume><number>3</number><keywords><keyword>Autopsy</keyword><keyword>Biopsy/methods</keyword><keyword>Brain/ pathology</keyword><keyword>Brain Diseases/ pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Postmortem Changes</keyword></keywords><dates><year>2007</year><pub-dates><date>May</date></pub-dates></dates><isbn>1090-3798 (Print)</isbn><accession-num>17270474</accession-num><urls></urls><research-notes>Case report</research-notes></record></Cite></EndNote>7,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaGF5eWlsPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

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ADDIN EN.CITE.DATA 8. However, it remains uncertain whether ante-mortem ischemic changes can be reliably distinguished from changes occurring post-mortem.The aim of this study was therefore to examine whether quantitative MR measurements can distinguish ante-mortem ischemic brain injury from post-mortem artifacts on post-mortem MRI.METHODSThis was a nested study as part of a large prospective study (MaRIAS– Magnetic Resonance Imaging Autopsy Study) comparing PM MRI with conventional autopsy in newborns ADDIN EN.CITE <EndNote><Cite><Author>Thayyil</Author><Year>2009</Year><RecNum>754</RecNum><DisplayText><style face="superscript">9</style></DisplayText><record><rec-number>754</rec-number><foreign-keys><key app="EN" db-id="varp2e5agaw2phezrf2xzdekee5twfzzat9f">754</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Thayyil, S.</author><author>Robertson, N. J.</author><author>Chitty, L. S.</author><author>Sebire, N. J.</author><author>Taylor, A. M.</author></authors></contributors><titles><title>Protocol 08PRT/5409: Postmortem magnetic resonance imaging in the fetus, infant, and child: a comparative study with conventional autopsy (UKCRN: 6794)</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>. The PM brain MRIs of seven infants who died following documented clinical neonatal encephalopathy (NE) of presumed hypoxic-ischemic origin were compared with those of seven infants who had sudden unexpected and unexplained death in the first seven days of life (SUND control)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWJlcjwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 10 without histological evidence of hypoxic-ischemic brain injury at autopsy. Infants with well-known risk factors, e.g., prematurity (<35 week gestation), perinatal asphyxia, or congenital malformations were classified as expected neonatal deaths and excluded PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWJlcjwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 10.The NE cases and controls had matched gestation, post-mortem interval to MRI, and age at death. The MRI changes in the control group were therefore presumed to reflect post-mortem changes that have no clinical significance.All scans were performed on a 1.5 Tesla MRI scanner (Siemens Avanto, Erlangen, Germany) using the same circularly polarized extremity coil. The following sequences were reported; 3D T1-weighted fast low angle shot (FLASH), 3D constructive interference in the steady state (CISS), 2D T2* weighted gradient echo, 2D diffusion-weighted imaging (DWI), and 2D T2-weighted dual echo short tau inversion recovery (DESTIR). All 2D images were acquired in the axial plane [Table 1]. The bodies were kept in the mortuary at 4 0C and transported to the adjacent MR facility immediately prior to the MR scan. A neonatologist with seven years of experience in post-mortem MRI and masked to the clinical history and autopsy findings reported the scans for evidence of hypoxic ischemic brain injury according to the scoring system described by Rutherford et al. PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SdXRoZXJmb3JkPC9BdXRob3I+PFllYXI+MTk5ODwvWWVh

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ADDIN EN.CITE.DATA 13.T1-weighted intensity values were normalized to ocular vitreous signal intensity on the same image and analyzed as ratios (SIRs) to minimize differences in scaling, coil loading or other acquisition conditions, which affect signal intensity ADDIN EN.CITE <EndNote><Cite><Author>Coskun</Author><Year>2001</Year><RecNum>118</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>118</rec-number><foreign-keys><key app="EN" db-id="t2z5f0da8z9x2jesp52xvtaird5tt2rpedre" timestamp="1413732834">118</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Coskun, A.</author><author>Lequin, M.</author><author>Segal, M.</author><author>Vigneron, D. B.</author><author>Ferriero, D. M.</author><author>Barkovich, A. J.</author></authors></contributors><auth-address>Department of Radiology, University of California, San Francisco 94143, USA.</auth-address><titles><title>Quantitative analysis of MR images in asphyxiated neonates: correlation with neurodevelopmental outcome</title><secondary-title>AJNR Am J Neuroradiol</secondary-title><alt-title>AJNR. American journal of neuroradiology</alt-title></titles><periodical><full-title>AJNR Am J Neuroradiol</full-title><abbr-1>AJNR. American journal of neuroradiology</abbr-1></periodical><alt-periodical><full-title>AJNR Am J Neuroradiol</full-title><abbr-1>AJNR. American journal of neuroradiology</abbr-1></alt-periodical><pages>400-5</pages><volume>22</volume><number>2</number><keywords><keyword>Asphyxia Neonatorum/*diagnosis</keyword><keyword>Brain/growth &amp; development/*pathology/physiopathology</keyword><keyword>*Child Development</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>*Magnetic Resonance Imaging</keyword><keyword>Motor Activity</keyword><keyword>Neurologic Examination</keyword><keyword>Reference Values</keyword></keywords><dates><year>2001</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0195-6108 (Print)&#xD;0195-6108 (Linking)</isbn><accession-num>11156790</accession-num><urls><related-urls><url>. ADC values were obtained by tracing ROIs on the DESTIR images, on which the corresponding ADC maps were overlaid (Convert3D v1.0). The following equation was used to calculate T2 relaxation times using the same ROI placed on both DESTIR images PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LdW1hcjwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 17,18:T2 = (TE2-TE1)/ln(SI1/SI2)where TE1 and TE2 are the echo times for the DESTIR images, and SI1 and SI2 represent the corresponding signal intensities in the region of interest. Standard full autopsy was performed after MRI, including neuropathological examination by specialist pediatric pathologists masked to the MRI results with both macroscopic and microscopic examination to include multiple regions of cortex, white matter, deep gray matter and posterior fossa structures. We did not co-register histological regions and MR ROI. Paraffin sections were stained by haematoxylin and eosin. Neuronal eosinophilia and karyorrhexis, astrocyte gliosis, activated microglia, accumulation of macrophages and hemorrhage were regarded as histopathological features of ischemic injury PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TcXVpZXI8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 1. Only cases that had a normal neuropathological examination were included in the SUND controls. Neonatal encephalopathy cases all had evidence of ischemic injury as above on neuropathological examination. STATISTICAL ANALYSIS: The Mann-Whitney U test was used for comparison of distributions between groups. p<0.05 was considered significant. Exact confidence intervals based on the F-distribution were calculated for diagnostic indices. (SPSS Version 17, SPSS Inc). RESULTSMedian gestational age, age at death, birth weight, and death-to-MRI interval were not significantly different between NE and SUND groups [Table 2]. Body temperature (axilla) was measured in eight infants; the median (range) temperature was 7.2 0C (6.9 0C to 8.8 0C) at the start of the scan.The signal intensities of left and right brain regions were not significantly different; therefore, we used mean values for analysis. There were no differences in mean T1-weighted SIRs, T2 relaxation times and ADC values in the predefined brain areas between NE and SUND (control) infants [Figure 2 a-b-c].PM MRI showed diffuse high signal intensities in T2-weighted images and lack of gray-white matter contrast in all SUND and NE infants. High signal intensity in the PLIC, commonly seen in ante-mortem T1-weighted images in healthy newborns, was absent in all SUND and NE cases [Table3]. All diffusion-weighted images showed generalized reduced diffusion; no focal lesions were seen [Figure 3]. DISCUSSIONThe findings of this study demonstrate that based on current protocols, PM MRI cannot reliably differentiate ante-mortem hypoxic ischemic brain injury from post-mortem changes, either on visual examination of images or by the use of quantitative MRI measurements on T1- or T2-weighted images and diffusion-weighted imaging. The T2 relaxation times in various brain regions were similar between NE and SUND infants. These observations suggest that possible hypoxic ischemic changes - occurring either as a part of the death process or post-mortem - are difficult to identify from ante-mortem ischemic injury using post-mortem MRI. Radiologists reporting post-mortem MRI examinations should be cautious of interpreting ante-mortem ischemic injury, since this may have medico-legal implications. Although ADC values have been reported in previous study to be reduced after NE in ante-mortem MRI ADDIN EN.CITE <EndNote><Cite><Author>Hunt</Author><Year>2004</Year><RecNum>14</RecNum><DisplayText><style face="superscript">20</style></DisplayText><record><rec-number>14</rec-number><foreign-keys><key app="EN" db-id="2tsdee0r7zwrzmedwtpx2wwqd9r5rxffrfrv">14</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hunt, R. W.</author><author>Neil, J. J.</author><author>Coleman, L. T.</author><author>Kean, M. J.</author><author>Inder, T. E.</author></authors></contributors><auth-address>Department of Neonatal Neurology, Royal Children&apos;s Hospital, Murdoch Children&apos;s Research Institute, University of Melbourne, Melbourne, Australia.</auth-address><titles><title>Apparent diffusion coefficient in the posterior limb of the internal capsule predicts outcome after perinatal asphyxia</title><secondary-title>Pediatrics</secondary-title></titles><periodical><full-title>Pediatrics</full-title><abbr-1>Pediatrics</abbr-1></periodical><pages>999-1003</pages><volume>114</volume><number>4</number><edition>2004/10/07</edition><keywords><keyword>Asphyxia Neonatorum/metabolism</keyword><keyword>Developmental Disabilities/classification/etiology</keyword><keyword>Diffusion</keyword><keyword>Humans</keyword><keyword>Hypoxia-Ischemia, Brain/complications/diagnosis/ metabolism/mortality</keyword><keyword>Infant, Newborn</keyword><keyword>Internal Capsule/ metabolism</keyword><keyword>Magnetic Resonance Imaging/methods</keyword><keyword>Paralysis/classification/ etiology</keyword><keyword>Prognosis</keyword><keyword>ROC Curve</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Severity of Illness Index</keyword></keywords><dates><year>2004</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1098-4275 (Electronic)</isbn><accession-num>15466097</accession-num><urls></urls><electronic-resource-num>114/4/999 [pii]&#xD;10.1542/peds.2003-0935-L [doi]</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>eng</language></record></Cite></EndNote>20, the current data show that ADC values were not different in NE and SUND cases. However, a five-fold reduction in ADC values was seen in the post-mortem MRI cases compared to previously described ante-mortem scans. The marked reduction of ADC values in this study is related to the low body temperature at the time of scanning, and tissue changes after death. This observation is consistent with recent post-mortem data from adult brainsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb2JheWFzaGk8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFy

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ADDIN EN.CITE.DATA 21 and with experimental evidence ADDIN EN.CITE <EndNote><Cite><Author>Shepherd</Author><Year>2009</Year><RecNum>767</RecNum><DisplayText><style face="superscript">22</style></DisplayText><record><rec-number>767</rec-number><foreign-keys><key app="EN" db-id="varp2e5agaw2phezrf2xzdekee5twfzzat9f">767</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shepherd, T. M.</author><author>Flint, J. J.</author><author>Thelwall, P. E.</author><author>Stanisz, G. J.</author><author>Mareci, T. H.</author><author>Yachnis, A. T.</author><author>Blackband, S. J.</author></authors></contributors><auth-address>Department of Radiology and Biomedical Imaging, University of California-San Francisco, San Francisco, CA 94143-0628, USA. tim.shepherd@radiology.ucsf.edu</auth-address><titles><title>Postmortem interval alters the water relaxation and diffusion properties of rat nervous tissue--implications for MRI studies of human autopsy samples</title><secondary-title>Neuroimage</secondary-title></titles><periodical><full-title>Neuroimage</full-title></periodical><pages>820-6</pages><volume>44</volume><number>3</number><keywords><keyword>Animals</keyword><keyword>Artifacts</keyword><keyword>Autopsy/methods</keyword><keyword>Body Water/ metabolism</keyword><keyword>Cerebral Cortex/ anatomy &amp; histology/ metabolism</keyword><keyword>Diffusion</keyword><keyword>Diffusion Magnetic Resonance Imaging/ methods</keyword><keyword>Humans</keyword><keyword>Image Enhancement/methods</keyword><keyword>Male</keyword><keyword>Postmortem Changes</keyword><keyword>Rats</keyword><keyword>Reproducibility of Results</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Specimen Handling/ methods</keyword><keyword>Time Factors</keyword></keywords><dates><year>2009</year><pub-dates><date>Feb 1</date></pub-dates></dates><isbn>1095-9572 (Electronic)&#xD;1053-8119 (Linking)</isbn><accession-num>18996206</accession-num><urls></urls></record></Cite></EndNote>22. The role of conventional PM MRI to identify ante-mortem hypoxic ischemic injury has been controversial in the published literature to date. Nicholl and colleagues reported PM MRI in six babies with NE and concluded that PM MRI could diagnose ante-mortem hypoxic ischemic injury. However, in that study brain histology was performed in only one case, and importantly, there were no control cases without NE and the radiologists were not blinded to the clinical findings ADDIN EN.CITE <EndNote><Cite><Author>Nicholl</Author><Year>2007</Year><RecNum>138</RecNum><DisplayText><style face="superscript">7</style></DisplayText><record><rec-number>138</rec-number><foreign-keys><key app="EN" db-id="varp2e5agaw2phezrf2xzdekee5twfzzat9f">138</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nicholl, R. M.</author><author>Balasubramaniam, V. P.</author><author>Urquhart, D. S.</author><author>Sellathurai, N.</author><author>Rutherford, M. A. Comment</author></authors></contributors><auth-address>Neonatal Unit, Northwick Park Hospital, North West London Hospitals NHS Trust, London, UK. richard.nicholl@nwlh.nhs.uk</auth-address><titles><title>Postmortem brain MRI with selective tissue biopsy as an adjunct to autopsy following neonatal encephalopathy</title><secondary-title>Eur J Paediatr Neurol</secondary-title></titles><periodical><full-title>Eur J Paediatr Neurol</full-title></periodical><pages>167-74</pages><volume>11</volume><number>3</number><keywords><keyword>Autopsy</keyword><keyword>Biopsy/methods</keyword><keyword>Brain/ pathology</keyword><keyword>Brain Diseases/ pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Postmortem Changes</keyword></keywords><dates><year>2007</year><pub-dates><date>May</date></pub-dates></dates><isbn>1090-3798 (Print)</isbn><accession-num>17270474</accession-num><urls></urls><research-notes>Case report</research-notes></record></Cite></EndNote>7. Cohen and colleagues also reported that PM MRI can detect ante-mortem hypoxic ischemic changes, and again the radiologists were not blinded to clinical history and no comparison was made with babies without ischemic injury ADDIN EN.CITE <EndNote><Cite><Author>Cohen</Author><Year>2007</Year><RecNum>561</RecNum><DisplayText><style face="superscript">23</style></DisplayText><record><rec-number>561</rec-number><foreign-keys><key app="EN" db-id="varp2e5agaw2phezrf2xzdekee5twfzzat9f">561</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cohen, M.</author><author>Whitby, E. H.</author></authors></contributors><titles><title>The use of magnetic resonance in the hospital and coronial pediatric postmortem examination</title><secondary-title>Forensic Sci Med Pathol</secondary-title></titles><periodical><full-title>Forensic Sci Med Pathol</full-title></periodical><pages>289-296</pages><volume>3</volume><dates><year>2007</year></dates><urls></urls></record></Cite></EndNote>23. Our findings support that suggestion that the differentiation of ante-mortem hypoxic ischemic brain injury from post-mortem artifacts is challenging on conventional MRI. In fact, the loss of high signal intensity in the PLIC on T1-weighted images and loss of gray-white matter differentiation, which are signs suggestive of perinatal asphyxia in ante-mortem MRI, also occur following sudden deaths due to many causes and in this postmortem setting do not necessarily indicate ischemic brain injury. Nevertheless, whilst T1-weighted PM MRI may suffer from the lack of contrast, this sequence may still have an important role in NE for excluding other brain abnormalities such as structural abnormalities and intracranial bleeds ADDIN EN.CITE <EndNote><Cite><Author>Thayyil</Author><Year>2010</Year><RecNum>819</RecNum><DisplayText><style face="superscript">5</style></DisplayText><record><rec-number>819</rec-number><foreign-keys><key app="EN" db-id="varp2e5agaw2phezrf2xzdekee5twfzzat9f">819</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Thayyil, S.</author></authors></contributors><titles><title>Less invasive autopsy: an evidenced based approach</title><secondary-title>Arch Dis Child</secondary-title></titles><periodical><full-title>Arch Dis Child</full-title></periodical><pages>Jun 1; Epub ahead of print</pages><dates><year>2010</year><pub-dates><date>Jun 1</date></pub-dates></dates><isbn>1468-2044 (Electronic)&#xD;0003-9888 (Linking)</isbn><accession-num>20515965</accession-num><urls></urls></record></Cite></EndNote>5, providing complimentary information to T2-weighted PM MRI. Specific post-mortem MRI scoring systems are required to be developed and evaluated for accurate identification of ante-mortem ischemic injury. Future studies of this nature should rely on the use of reproducible, quantitative measures derived from imaging, and perhaps the use of MR spectroscopy to give insight into the associated changes in tissue metabolite content.Our study has some limitations. Firstly, we did not measure the body temperature in all of the infants at the time of MR scan, nevertheless all infants were scanned under similar conditions, having been in standard mortuary refrigeration storage until immediately prior to the scan. Therefore the body temperature is likely to similar and less than 100C in all infants. Secondly, it is possible that the changes on PM MRI are related to the post-mortem interval. It could be speculated that if PM MRI had been performed immediately after death, detection of ischemic injury may be accurate, with less secondary post-mortem change. However, for service reasons the scans (and autopsies) in this study were performed between 2-5 days after death. Whilst this did not allow us to evaluate the effect of short PM intervals, this does represent a realistic post-mortem interval in routine clinical practice for performing PM MRI and perinatal / infant autopsies, hence the findings are generalizable within this period. Thirdly, we did not attempt co-registration of MRI and histological regions due to difficulties in recording the sampling coordinates precisely, however PM MRI abnormalities were generalized in all cases. Fourth, we used the standard clinical ante-mortem MR sequences and did not optimize these for post-mortem use. T1-weighted images provided very minimal contrast; nevertheless good contrast was seen in T2– weighted and proton density sequences. It is possible that further optimization of MR sequences can improve the contrast and diagnostic accuracy, however such optimization is challenging due to change in T1 and T2 after death PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaGF5eWlsPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

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ADDIN EN.CITE.DATA 24.Finally, the sample size is relatively small and a histological grading and classification of the hypoxic ischemic injury was not performed. Although subtle differences may have been missed, the interpretation was performed in a similar manner to evaluation of cranial MRI in life in terms of lesion detection and evaluation. In summary, distinguishing ante-mortem hypoxic ischemic brain injury from post-mortem change is difficult on routine PM MRI, despite the use of quantitative MRI measurements derived from T1 and T2-weighted images and diffusion-weighted imaging. These ‘normal’ post-mortem changes may be mistakenly classified as ante-mortem ischemic injury, which may have medico-legal implications. There is a need for the development of additional imaging techniques to reliably identify postmortem change from preceding hypoxic ischemic brain injury in this clinical setting. FundingThe study was funded by UK Department of Health Research Programme, and Biomedical Research Centre, Imperial College London. The study sponsors had no role in the design or conduct of the study, in the collection, analysis, or interpretation of the data, or in the writing of the report. ST is funded by a clinician scientist award from the National Institute of Health Research.REFERENCES ADDIN EN.REFLIST 1.Squier W, Cowan FM. The value of autopsy in determining the cause of failure to respond to resuscitation at birth. Seminars in neonatology : SN 2004;9:331-45.2.Kurinczuk JJ, White-Koning M, N B. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early Hum Dev 2010;86:329-38.3.Confidential Enquiry into Maternal and Child Health: Perinatal Mortality. wwwcmaceorguk/getattachment//Perinatal-Mortality-2007aspx (accessed 2512010) 2009:London.4.Breeze AC, Jessop FA, Set PA, et al. 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Multiparametric quantitation of the perilesional region in patients with healed or healing solitary cysticercus granuloma. NeuroImage 2002;15:1015-20.18.Duncan JS, Bartlett P, Barker GJ. Technique for measuring hippocampal T2 relaxation time. AJNR American journal of neuroradiology 1996;17:1805-10.19.Gutierrez LG, Rovira A, Portela LA, Leite Cda C, Lucato LT. CT and MR in non-neonatal hypoxic-ischemic encephalopathy: radiological findings with pathophysiological correlations. Neuroradiology 2010;52:949-76.20.Hunt RW, Neil JJ, Coleman LT, Kean MJ, Inder TE. Apparent diffusion coefficient in the posterior limb of the internal capsule predicts outcome after perinatal asphyxia. Pediatrics 2004;114:999-1003.21.Kobayashi T, Shiotani S, Kaga K, et al. Characteristic signal intensity changes on postmortem magnetic resonance imaging of the brain. Japanese journal of radiology 2010;28:8-14.22.Shepherd TM, Flint JJ, Thelwall PE, et al. 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