Sudhin Thayyil

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.

Post mortem magnetic resonance imaging in the fetus, infant and child: a comparative study with conventional autopsy (MaRIAS Protocol).

BackgroundMinimally invasive autopsy by post mortem magnetic resonance (MR) imaging has been suggested as an alternative for conventional autopsy in view of the declining consented autopsy rates. However, large prospective studies rigorously evaluating the accuracy of such an approach are lacking. We intend to compare the accuracy of a minimally invasive autopsy approach using post mortem MR imaging with that of conventional autopsy in fetuses, newborns and children for detection of the major pathological abnormalities and/or determination of the cause of death.Methods/DesignWe recruited 400 consecutive fetuses, newborns and children referred for conventional autopsy to one of the two participating hospitals over a three-year period. We acquired whole body post mortem MR imaging using a 1.5 T MR scanner (Avanto, Siemens Medical Solutions, Enlargen, Germany) prior to autopsy. The total scan time varied between 90 to 120 minutes. Each MR image was reported by a team of four specialist radiologists (paediatric neuroradiology, paediatric cardiology, paediatric chest & abdominal imaging and musculoskeletal imaging), blinded to the autopsy data. Conventional autopsy was performed according to the guidelines set down by the Royal College of Pathologists (UK) by experienced paediatric or perinatal pathologists, blinded to the MR data. The MR and autopsy data were recorded using predefined categorical variables by an independent person.DiscussionUsing conventional post mortem as the gold standard comparator, the MR images will be assessed for accuracy of the anatomical morphology, associated lesions, clinical usefulness of information and determination of the cause of death. The sensitivities, specificities and predictive values of post mortem MR alone and MR imaging along with other minimally invasive post mortem investigations will be presented for the final diagnosis, broad diagnostic categories and for specific diagnosis of each system.Clinical Trial RegistrationNCT01417962NIHR Portfolio Number: 6794

Therapeutic hypothermia for neonatal encephalopathy in low- and middle-income countries: a systematic review and meta-analysis.

Although selective or whole body cooling combined with optimal intensive care improves outcomes following neonatal encephalopathy in high-income countries, the safety and efficacy of cooling in low-and middle-income countries is not known. Objective We performed a systematic review and meta-analysis of all published randomised or quasi-randomised controlled trials of cooling therapy for neonatal encephalopathy in low-and middle-income countries. Results Seven trials, comprising a total of 567 infants were included in the meta-analysis. Most study infants had mild (15%) or moderate encephalopathy (48%) and did not receive invasive ventilation (88%). Cooling devices included water-circulating cooling caps, frozen gel packs, ice, water bottles, and phase-changing material. No statistically significant reduction in neonatal mortality was seen with cooling (risk ratio: 0.74, 95% confidence intervals: 0.44 to 1.25). Data on other neonatal morbidities and long-term neurological outcomes were insufficient. Conclusion Cooling therapy was not associated with a statistically significant reduction in neonatal mortality in low-and middle-income countries although the confidence intervals were wide and not incompatible with results seen in high-income countries. The apparent lack of treatment effect may be due to the heterogeneity and poor quality of the included studies, inefficiency of the low technology cooling devices, lack of optimal neonatal intensive care, sedation and ventilatory support, overuse of oxygen, or may be due to the intrinsic difference in the population, for example higher rates of perinatal infection, obstructed labor, intrauterine growth retardation and maternal malnutrition. Evaluation of the safety and efficacy of cooling in adequately powered randomised controlled trials is required before cooling is offered in routine clinical practice in low-and middle-income countries.

Diagnostic accuracy of post-mortem magnetic resonance imaging in fetuses, children and adults: A systematic review

To determine, in a systematic review, the diagnostic accuracy, acceptability and cost-effectiveness of less invasive autopsy by post-mortem MR imaging, in fetuses, children and adults. We searched Medline, Embase, the Cochrane library and reference lists to identify all studies comparing post-mortem MR imaging with conventional autopsy, published between January 1990 and March 2009. 539 abstracts were identified; 15 papers met the inclusion criteria; data from 9 studies were extracted (total: 146 fetuses, 11 children and 24 adults). In accurately identifying the final cause of death or most clinically significant abnormality, post-mortem MR imaging had a sensitivity and specificity of 69% (95% CI-56%, 80%) and 95% (95% CI-88%, 98%) in fetuses, and 28% (95% CI-13%, 47%) and 64% (95% CI-23%, 94%) in children and adults, respectively; however the published data is limited to small, heterogenous and poorly designed studies. Insufficient data is available on acceptability and economic evaluation of post-mortem MR imaging. Well designed, large, prospective studies are required to evaluate the accuracy of post-mortem MR imaging, before it can be offered as a clinical tool.

Minimally invasive perinatal autopsies using magnetic resonance imaging and endoscopic postmortem examination ("keyhole autopsy"): feasibility and initial experience

Objective: Perinatal autopsy provides additional diagnostic information in a significant proportion of cases but parents and relatives frequently decline traditional postmortem (PM) examination, partly due to the unacceptability of the cosmetic effects of large incisions and concerns regarding organ retention. We present a novel minimally invasive autopsy method for fetal and neonatal PMexaminations, which includes PM magnetic resonance imaging (MRI) for assessment of anatomy and endoscopic internal examination to allow direct organ visualization and targeted tissue biopsy. Methods: Descriptive retrospective feasibility report of the first 10 perinatal cases undergoing endoscopic minimally invasive autopsy. Results: A minimally invasive autopsy (MIA) approach based on postmortem MRI (PM MRI) and endoscopic autopsy with tissue biopsy is feasible and effective with minimal cosmetic consequences compared to traditional PM examination. Endoscopic examination with tissue biopsy provided additional diagnostic information to PM MRI alone in the majority of cases. Conclusions: Endoscopic MIA is a feasible and potentially more acceptable approach to perinatal autopsy and provides an additional option for parents who do not agree to a traditional PM examination. This approach could result in increased utilization of investigations after death in this group of patients.

Minimally invasive fetal postmortem examination using magnetic resonance imaging and computerised tomography: current evidence and practical issues

For a variety of reasons, acceptance of traditional postmortem examination following foetal or neonatal death has declined significantly in recent years in the UK. Here, we review the case for the development of less invasive autopsy using combined investigations including imaging techniques, in particular, magnetic resonance imaging and computerised tomography. Copyright

Acceptability of a minimally invasive perinatal/paediatric autopsy: healthcare professionals' views and implications for practice

Perinatal autopsy provides essential clinical information, including cause of death; yet, autopsy rates have steadily declined because of parental refusal. Technology now enables less invasive alternatives to traditional autopsy and may increase the acceptability of post‐mortem examination.

Techniques for therapeutic hypothermia during transport and in hospital for perinatal asphyxial encephalopathy

Over the past 10 years, several randomised clinical trials of therapeutic hypothermia for perinatal asphyxial encephalopathy have demonstrated both safety and efficacy of therapeutic hypothermia in improving neurological outcome. Today cooling is increasingly used in tertiary level units throughout the developed world. Therapeutic hypothermia (cooling to a rectal or core temperature of 33-34 degrees C for 72 h) is easier to achieve in newborn infants than in adults. There is a natural tendency for the core temperature of infants who suffered birth asphyxia to fall and remain lower than non-asphyxiated infants for up to 16 h after birth. A variety of high- and low-tech surface cooling methods have been used in neonates - newer systems are servo-controlled and provide very stable temperature control. It is well accepted that to be most effective, cooling needs to be initiated as soon as possible after birth and, thus, needs to be commenced prior to the transfer of infants to cooling centres. We describe our experience of passive cooling before and during the transfer of infants with encephalopathy to cooling centres in a major city in the UK.

A semi-automated method for non-invasive internal organ weight estimation by post-mortem magnetic resonance imaging in fetuses, newborns and children.

UNLABELLED Magnetic resonance (MR) imaging allows minimally invasive autopsy, especially when consent is declined for traditional autopsy. Estimation of individual visceral organ weights is an important component of traditional autopsy. OBJECTIVE To examine whether a semi-automated can be used for non-invasive internal organ weight measurement using post-mortem MR imaging in fetuses, newborns and children. METHODS Phase 1: In vitro scanning of 36 animal organs (heart, liver, kidneys) was performed to check the accuracy of volume reconstruction methodology. Real volumes were measured by water displacement method. Phase 2: Sixty-five whole body post-mortem MR scans were performed in fetuses (n=30), newborns (n=5) and children (n=30) at 1.5T using a 3D TSE T2-weighted sequence. These data were analysed offline using the image processing software Mimics 11.0. RESULTS Phase 1: Mean difference (S.D.) between estimated and actual volumes were -0.3 (1.5)ml for kidney, -0.7 (1.3)ml for heart, -1.7 (3.6)ml for liver in animal experiments. Phase 2: In fetuses, newborns and children mean differences between estimated and actual weights (S.D.) were -0.6 (4.9)g for liver, -5.1 (1.2)g for spleen, -0.3 (0.6)g for adrenals, 0.4 (1.6)g for thymus, 0.9 (2.5)g for heart, -0.7 (2.4)g for kidneys and 2.7 (14)g for lungs. Excellent co-correlation was noted for estimated and actual weights (r(2)=0.99, p<0.001). Accuracy was lower when fetuses were less than 20 weeks or less than 300g. CONCLUSION Rapid, accurate and reproducible estimation of solid internal organ weights is feasible using the semi-automated 3D volume reconstruction method.

Prospective parental consent for autopsy research following sudden unexpected childhood deaths: a successful model

Background: Organ retention issues, recent changes in the Coroners’ (Amendment) Rules 2005 and the Human Tissue Act have resulted in pessimism regarding prospective consent for paediatric autopsy research in the UK. Objectives: To examine the feasibility and acceptability of a prospective telephone consenting model for post-mortem magnetic resonance (MR) imaging research in HM Coroners’ cases. Design: Following each autopsy referral from the HM Coroner, permission to contact the family for research was requested. A family liaison sister, with experience in dealing with bereaved families, then contacted the parents by telephone, explained the study and obtained oral, and then written consent for post-mortem imaging. Setting: London and an area south of London. Results: Of 76 eligible HM Coroners’ cases referred during the study period, permission to contact parents (provided by the HM Coroners’ Office) was obtained for only 32 cases (42%). The research sister contacted 32 parents during the study period of whom 31 (96.8%) gave oral research consent. “Helping other parents in the future” and “the importance of post-mortem research” were the main reasons for parents wanting to participate in research. Conclusions: Prospective consenting for HM Coroners’ cases for research is feasible in children, and can be done ethically by parental consenting via telephone contact before autopsy by appropriately trained staff. However, close co-ordination between mortuary staff, HM Coroners, research staff and medical staff is required. This model may be useful in performing post-mortem research in HM Coroners’ cases and in developing paediatric tissue and brain banks in the UK.