Detecting the cause of death in infants and children: Whole body post-mortem computed tomography compared to autopsy. Thesis submitted for the degree of Doctor of Philosophy by Mohamed Mohamed Ben Taher Supervised by Drs. Amaka C Offiah & Marta C Cohen Department of Oncology & Metabolism Medical School October 2018 1 Conferences and publication arising from this thesis Published paper: Mohamed Ben Taher; Jean Russell; Marta C Cohen; Amaka C. Offiah (Acceptability of post-mortem imaging among Muslim and non-Muslim communities) has been published in the British Journal of Radiology (BJR) https://doi.org/10.1259/bjr.20180295 https://www.auntminnie.com/index.aspx?sec=ser&sub=def&pag=dis&ItemID=1177 01 Paper undergoing peer-review: Mohamed Ben Taher; Timothy M. Skerry; Jean Russell; Marta C Cohen; Amaka C. Offiah. Non-Invasive Estimation of Post-Mortem Interval using Computed Tomography, Submitted to International Journal of Legal Medicine. Podium (oral) presentation: Mohamed Ben Taher; Timothy M. Skerry; Jean Russell; Marta C Cohen; Amaka C. Offiah. Non-Invasive Estimation of Post-Mortem Interval using Computed Tomography. 40th Post Graduate Course & 54th Annual Meeting of the European Society of Paediatric Radiology (ESPR 2018). Abstract published in Pediatric Radiology 2018. 421-422. Berlin. Germany. 2 Posters: Mohamed Ben Taher; Marta Cohen; Amaka C Offiah. The role of whole-body post- mortem CT scan in the detection of causes of unexpected infant death. 6th Annual Mellanby Centre Research Day, Sheffield, UK Mohamed Ben Taher; Marta Cohen; Amaka C Offiah. Is Post-mortem Imaging Acceptable to the Libyan Community? 7th Annual Mellanby Centre Research Day, Sheffield, UK Mohamed Ben Taher; Marta Cohen; Amaka C Offiah. Is post-mortem imaging acceptable to the Libyan community? UKRC Congress 2017, Manchester, UK. Mohamed Ben Taher; Timothy M. Skerry; Jean Russell; Marta C Cohen; Amaka C. Offiah. Estimating time of death using post-mortem computed tomography. BSPR National Meeting 2017, Manchester, UK 3 Acknowledgments In the name of Allah, the most Gracious, the most Merciful. Thanks be to Allah for giving me enough strength and the blessing to complete this thesis. First, I would like to express my deepest gratitude to my supervisors, Dr. Amaka C Offiah and Dr. Marta Cohen, for their patience, continuous support and unlimited encouragement throughout my period of study. I would also like to thank them for their help and dedicated involvement in every step of the process of preparing this report. Without their support and guidance more than four years of this study. I would also like to give my gratitude to my main tutor, Dr. Peter S Grabowski, for his supervision during this time. I also appreciate the financial support of the Libyan Ministry of Higher Education. My appreciation and thanks extend to Elzene Kruger, Jennifer Simpson and the staff of the Department of Radiology, Sheffield Children’s Hospital who supported me to finish this study. My thanks are extended to Dr. Darren Robinson, Light Microscopy Facility Manager, Department of Biomedical Science, who provided me with training in using the ImageJ software to measure air volume. I would also like to thank my friend Dr. Gnadi Zwawe for helping transport the dead lambs to scan and also for his support during many difficult periods during my study and thesis preparation. 4 Abstract Post-mortem investigation is a sensitive issue that needs to be studied in order to address the many issues that surround this topic. This thesis is divided into 7 chapters. Chapter One is a review of the literature, providing information about identifying the causes of death in children, autopsy protocols and the acceptability of post-mortem investigations among the public. Chapter Two determined the reaction towards post- mortem procedures among Muslims and non-Muslims in Libya and in the UK. Muslims were found to have a significant preference for post-mortem imaging compared to autopsy except in homicidal cases. Chapter Three is a systematic review of the literature which identified 3 papers totalling 262 patients and showed overall agreement between post-mortem CT and conventional autopsy of 51%. Chapter Four is an evaluation of the performance of PMCT compared to conventional autopsy in identifying the cause of death in 54 infants and children. Conventional autopsy detected significantly more abnormalities than PMCT and proved to be superior to PMCT for identifying organ’ soft tissue abnormalities. PMCT however was superior at identifying skeletal pathology. Chapter Five investigated whether longitudinal changes in organ Hounsfield units (HU) and total body air volume (TBAV) can provide an estimate of post-mortem interval (PMI) in eight euthanised lambs. TBAV increased by 14 cm3 (p< 0.001) for each additional post-mortem day with an intercept of 116 cm3 (p< 0.001). There was clear and progressive decrease in tissue densities and increase in TBAV in individual cases over time. Chapter Six is a pilot study to determine whether PMCT can be used to estimate PMI in 51 infants and children by measuring HU of selected organs. Results suggest that further investigation of the reliability of using HU of the kidney and spleen to estimate PMI is warranted. Chapter Seven provides an overview, discussion and concludes this thesis. 5 Table of contents 1. Chapter One .................................................................................................. 13 Introduction ............................................................................................... 14 1.1.1 Objectives of the PhD project .............................................................. 19 Literature review, including methods of diagnosis and autopsy protocols 20 1.2.1 Diagnosis of causes of death in fetuses, infants and children .............. 20 1.2.2 Autopsy protocol .................................................................................. 29 1.2.3 Acceptability of Post-Mortem Imaging among Muslim and non-Muslim Communities ....................................................................................................... 38 1.2.4 Estimating duration of death ................................................................ 42 1.2.5 Conclusion ........................................................................................... 49 2. Chapter Two .................................................................................................. 51 Acceptability of Post-Mortem Imaging among Muslim and non-Muslim Communities ...................................................................................................... 52 2.1.1 Abstract ................................................................................................ 52 Introduction ................................................................................................. 54 Methods ....................................................................................................... 56 2.3.1 Study Design ........................................................................................ 56 2.3.2 Ethical approval and consent process .................................................. 57 Results ......................................................................................................... 57 Discussion ................................................................................................... 65 Conclusion ................................................................................................... 70 3. Chapter Three ............................................................................................... 71 Comparing the accuracy of post-mortem computed tomography with conventional autopsy in identifying the cause of death in infants and children: A systematic review .......................................................................... 72 6 3.1.1 Abstract ................................................................................................ 72 3.1.2 Introduction .......................................................................................... 74 3.1.3 Search strategy ..................................................................................... 76 3.1.4 Statistical analysis ................................................................................ 79 Summary of Studies .................................................................................... 82 Discussion ................................................................................................... 86 3.3.1 Limitations ........................................................................................... 88 Conclusion ................................................................................................... 88 4. Chapter Four ................................................................................................. 89 Evaluating the agreement between post-mortem computed tomography and conventional autopsy in infants and children ......................................... 90 4.1.1 Abstract ................................................................................................ 90 4.1.2 Introduction .......................................................................................... 92 4.1.3 Materials and methods ......................................................................... 94 4.1.4 Results .................................................................................................. 96 4.1.5 Results regarding the cause of death ...................................................