Publications
40 results found
Thayyil S, Montaldo P, Krishnan V, et al., 2023, Whole-body hypothermia, cerebral magnetic resonance biomarkers, and outcomes in neonates with moderate or severe hypoxic-ischemic encephalopathy born at tertiary care centers vs other facilities: a nested study within a randomized clinical trial, JAMA Network Open, Vol: 6, Pages: 1-16, ISSN: 2574-3805
Importance The association between place of birth and hypothermic neuroprotection after hypoxic-ischemic encephalopathy (HIE) in low- and middle-income countries (LMICs) is unknown.Objective To ascertain the association between place of birth and the efficacy of whole-body hypothermia for protection against brain injury measured by magnetic resonance (MR) biomarkers among neonates born at a tertiary care center (inborn) or other facilities (outborn).Design, Setting, and Participants This nested cohort study within a randomized clinical trial involved neonates at 7 tertiary neonatal intensive care units in India, Sri Lanka, and Bangladesh between August 15, 2015, and February 15, 2019. A total of 408 neonates born at or after 36 weeks’ gestation with moderate or severe HIE were randomized to receive whole-body hypothermia (reduction of rectal temperatures to between 33.0 °C and 34.0 °C; hypothermia group) for 72 hours or no whole-body hypothermia (rectal temperatures maintained between 36.0 °C and 37.0 °C; control group) within 6 hours of birth, with follow-up until September 27, 2020.Exposure 3T MR imaging, MR spectroscopy, and diffusion tensor imaging.Main Outcomes and Measures Thalamic N-acetyl aspartate (NAA) mmol/kg wet weight, thalamic lactate to NAA peak area ratios, brain injury scores, and white matter fractional anisotropy at 1 to 2 weeks and death or moderate or severe disability at 18 to 22 months.Results Among 408 neonates, the mean (SD) gestational age was 38.7 (1.3) weeks; 267 (65.4%) were male. A total of 123 neonates were inborn and 285 were outborn. Inborn neonates were smaller (mean [SD], 2.8 [0.5] kg vs 2.9 [0.4] kg; P = .02), more likely to have instrumental or cesarean deliveries (43.1% vs 24.7%; P = .01), and more likely to be intubated at birth (78.9% vs 29.1%; P = .001) than outborn neonates, although the rate of severe HIE was not different (23.6% vs 17.9%; P =&thin
Sveinsson B, Rowe OE, Stockmann JP, et al., 2022, Feasibility of simultaneous high-resolution anatomical and quantitative magnetic resonance imaging of sciatic nerves in patients with Charcot-Marie-Tooth type 1A (CMT1A) at 7T, Muscle and Nerve, Vol: 66, Pages: 206-211, ISSN: 0148-639X
Introduction/AimsMagnetic resonance imaging (MRI) of peripheral nerves can provide image-based anatomical information and quantitative measurement. The aim of this pilot study was to investigate the feasibility of high-resolution anatomical and quantitative MRI assessment of sciatic nerve fascicles in patients with Charcot–Marie–Tooth (CMT) 1A using 7T field strength.MethodsSix patients with CMT1A underwent imaging on a high-gradient 7T MRI scanner using a 28-channel knee coil. Two high-resolution axial images were simultaneously acquired using a quantitative double-echo in steady-state (DESS) sequence. By comparing the two DESS echoes, T2 and apparent diffusion coefficient (ADC) maps were calculated. The cross-sectional areas and mean T2 and ADC were measured in individual fascicles of the tibial and fibular (peroneal) portions of the sciatic nerve at its bifurcation and 10 mm distally. Disease severity was measured using Charcot–Marie–Tooth Examination Score (CMTES) version 2 and compared to imaging findings.ResultsWe demonstrated the feasibility of 7T MRI of the proximal sciatic nerve in patients with CMT1A. Using the higher field, it was possible to measure individual bundles in the tibial and fibular divisions of the sciatic nerve. There was no apparent correlation between diffusion measures and disease severity in this small cohort.DiscussionThis pilot study indicated that high-resolution MRI that allows for combined anatomical and quantitative imaging in one scan is feasible at 7T field strengths and can be used to investigate the microstructure of individual nerve fascicles.
Song Y, Lally PJ, Lopez MY, et al., 2022, Edited magnetic resonance spectroscopy in the neonatal brain, Neuroradiology: a journal devoted to neuroimaging and interventional neuroradiology, Vol: 64, Pages: 217-232, ISSN: 0028-3940
J-difference-edited spectroscopy is a valuable approach for the detection of low-concentration metabolites with magnetic resonance spectroscopy (MRS). Currently, few edited MRS studies are performed in neonates due to suboptimal signal-to-noise ratio, relatively long acquisition times, and vulnerability to motion artifacts. Nonetheless, the technique presents an exciting opportunity in pediatric imaging research to study rapid maturational changes of neurotransmitter systems and other metabolic systems in early postnatal life. Studying these metabolic processes is vital to understanding the widespread and rapid structural and functional changes that occur in the first years of life. The overarching goal of this review is to provide an introduction to edited MRS for neonates, including the current state-of-the-art in editing methods and editable metabolites, as well as to review the current literature applying edited MRS to the neonatal brain. Existing challenges and future opportunities, including the lack of age-specific reference data, are also discussed.
Evans M, Wade C, Hohenschurz-Schmidt D, et al., 2021, Magnetic resonance imaging as a biomarker in diabetic and HIV-associated peripheral neuropathy: A systematic review-based narrative, Frontiers in Neuroscience, Vol: 15, ISSN: 1662-453X
Background: Peripheral neuropathy can be caused by diabetes mellitus and HIV infection, and often leaves patients with treatment-resistant neuropathic pain. To better treat this condition, we need greater understanding of the pathogenesis, as well as objective biomarkers to predict treatment response. Magnetic resonance imaging (MRI) has a firm place as a biomarker for diseases of the central nervous system (CNS), but until recently has had little role for disease of the peripheral nervous system. Objectives: To review the current state-of-the-art of peripheral nerve MRI in diabetic and HIV symmetrical polyneuropathy. We used systematic literature search methods to identify all studies currently published, using this as a basis for a narrative review to discuss major findings in the literature. We also assessed risk of bias, as well as technical aspects of MRI and statistical analysis. Methods: Protocol was pre-registered on NIHR PROSPERO database. MEDLINE, Web of Science and EMBASE databases were searched from 1946 to 15th August 2020 for all studies investigating either diabetic or HIV neuropathy and MRI, focusing exclusively on studies investigating symmetrical polyneuropathy. The NIH quality assessment tool for observational and cross-sectional cohort studies was used for risk of bias assessment. Results: The search resulted in 18 papers eligible for review, 18 for diabetic neuropathy and 0 for HIV neuropathy. Risk of bias assessment demonstrated that studies generally lacked explicit sample size justifications, and some may be underpowered. Whilst most studies made efforts to balance groups for confounding variables (age, gender, BMI, disease duration), there was lack of consistencybetween studies. Overall, the literature provides convincing evidence that DPN is associated with larger nerve cross sectional area, T2-weighted hyperintense and hypointense lesions, evidence of nerve oedema on Dixon imaging, decreased fractional anisotropy and increased apparent dif
Thayyil S, Pant S, Montaldo P, et al., 2021, Hypothermia for moderate or severe neonatal encephalopathy in low and middle-income countries (HELIX): a randomised control trial in India, Sri Lanka and Bangladesh, The Lancet Global Health, Vol: 9, Pages: e1273-e1285, ISSN: 2214-109X
Background: Although therapeutic hypothermia reduces death or disability after neonatal encephalopathy in high-income countries, its safety and efficacy in low- and middle-income countries (LMICs) remains unclear. We examined if therapeutic hypothermia alongside optimal supportive intensive care reduces death or disability after neonatal encephalopathy in South Asia. Methods: We conducted a multi-country open label randomised controlled trial involving seven tertiary neonatal intensive care units in India, Sri Lanka and Bangladesh, between August 2015 and September 2020. We allocated infants born at or after 36 weeks of gestation with moderate or severe neonatal encephalopathy into whole body hypothermia (33·5 0 C) for 72 hours using a servo-controlled cooling device, or usual care (control group), within six hours of birth. All recruiting sites had facilities for invasive ventilation, cardiovascular support and access to 3 Telsa magnetic resonance imaging and spectroscopy. The primary outcome was a combined end point of death or moderate or severe disability at 18 to 22 months of age, assessed by Bayley scales of infant development (Version III).Findings: Of 576 eligible infants, we assigned 202 to hypothermia and 206 to control group. Primary outcome data were available for 394 (96·5%) infants, and occurred in 98(50·3%) of the hypothermia and 94 (47·2%) of the control group (Risk Ratio (RR) 1·06;95% confidence intervals (CI) 0·87 to 1·30 (p = 0·55). Eighty-four infants (42·4%) in the hypothermia group and 63 (31·3%) (p = 0·02) infants in the control group died, of whom 72 (35·6%) and 49 (23·8%) (p = 0·009) died during neonatal hospitalisation. Interpretation: Therapeutic hypothermia did not reduce the combined outcome of death or disability at18 months after neonatal encephalopathy in LMICs, but significantly increased mortality. Therapeutic hypothermia should not
Lally P, Matthews P, Bangerter N, 2021, Unbalanced SSFP for super-resolution in MRI, Magnetic Resonance in Medicine, Vol: 85, Pages: 2477-2489, ISSN: 0740-3194
Purpose: To achieve rapid, low SAR super-resolution imaging by exploiting the characteristic magnetization off-resonance profile in SSFP.Theory and Methods: In the presented technique, low flip angle unbalanced SSFP imaging is used to acquire a series of images at a low nominal resolution which are then combined in a super-resolution strategy analogous to non-linear structured illumination microscopy. This is demonstrated in principle via Bloch simulations and synthetic phantoms, and the performance is quantified in terms of point-spread function (PSF) and signal-to-noise ratio (SNR) for gray and white matter from field strengths of 0.35T to 9.4T. A k-space reconstruction approach is proposed to account for B0 effects. This was applied to reconstruct super-resolution images from a test object at 9.4T.Results: Artifact-free super-resolution images were produced after incorporating sufficient preparation time for the magnetization to approach the steady state. High-resolution images of a test object were obtained at 9.4T, in the presence of considerable B0 inhomogeneity. For gray matter, the highest achievable resolution ranges from 3% of the acquired voxel dimension at 0.35T, to 9% at 9.4T. For white matter, this corresponds to 3% and 10% respectively. Compared to an equivalent segmented gradient echo acquisition at the optimal flip angle, with a fixed TR of 8ms, gray matter has up to 34% of the SNR at 9.4T while using a x10 smaller flip angle. For white matter, this corresponds to 29% with a x11 smaller flip angle.Conclusion: This approach achieves high degrees of super-resolution enhancement with minimal RF power requirements.
Bourke N, Yanez-Lopez M, Jenkins P, et al., 2021, Traumatic brain injury: a comparison of diffusion and volumetric magnetic resonance imaging measures, Brain Communications, Vol: 3, ISSN: 2632-1297
Cognitive impairment following traumatic brain injury remains hard to predict. This is partly because axonal injury, which is of fundamental importance, is difficult to measure clinically. Advances in MRI allow axonal injury to be detected after traumatic brain injury, but the most sensitive approach is unclear. Here we compare the performance of diffusion tensor imaging, neurite orientation dispersion and density-imaging and volumetric measures of brain atrophy in the identification of white matter abnormalities after traumatic brain injury.Thirty patients with moderate-severe traumatic brain injury in the chronic phase and 20 age-matched controls had T1-weighted and diffusion MRI. Neuropsychological tests of processing speed, executive functioning and memory were used to detect cognitive impairment.Extensive abnormalities in neurite density index and orientation dispersion index were observed, with distinct spatial patterns. Fractional anisotropy and mean diffusivity also indicated widespread abnormalities of white matter structure. Neurite density index was significantly correlated with processing speed. Slower processing speed was also related to higher mean diffusivity in the cortico-spinal tracts. Lower white matter volumes were seen following brain injury with greater effect sizes compared to diffusion metrics however volume was not sensitive to changes in cognitive performance.Volume was the most sensitive at detecting change between groups but was not specific for determining relationships with cognition. Abnormalities in fractional anisotropy and mean diffusivity were the most sensitive diffusion measures, however neurite density index and orientation dispersion index may be more spatially specific. Lower neurite density index may be a useful metric for examining slower processing speed.
Montaldo P, Cunnington A, Oliveira V, et al., 2020, Transcriptomic profile of adverse neurodevelopmental outcomes after neonatal encephalopathy, Scientific Reports, Vol: 10, Pages: 1-7, ISSN: 2045-2322
A rapid and early diagnostic test to identify the encephalopathic babies at risk of adverse outcome may accelerate the development of neuroprotectants. We examined if a whole blood transcriptomic signature measured soon after birth,predicts adverse neurodevelopmental outcomeeighteenmonths after neonatal encephalopathy.We performed next generation sequencing on whole blood ribonucleic acid obtained within sixhours of birth from the first 47encephalopathic babies recruited to the Hypothermia for Encephalopathy in Low and middle-income countries (HELIX)trial. Two infants with blood culture positive sepsis were excluded, and the data from remaining 45 were analysed. A total of 855genes were significantly differentially expressed between the good and adverse outcome groups, of which RGS1and SMC4 werethe most significant. Biological pathway analysis adjusted for gender, trial randomisation allocation (cooling therapy versus usual care) and estimated blood leukocyte proportions revealed over-representation of genes from pathways related to melatoninand polo-like kinase in babieswith adverse outcome. These preliminary data suggest that transcriptomic profiling may be a promising tool for rapid risk stratification in neonatal encephalopathy. It may provide insights into biological mechanismsand identify novel therapeutic targetsfor neuroprotection.
Kariholu U, Montaldo P, Markati T, et al., 2020, Therapeutic hypothermia for mild neonatal encephalopathy: A systematic review and meta-analysis, Archives of Disease in Childhood. Fetal and Neonatal Edition, Vol: 105, Pages: 225-228, ISSN: 1359-2998
Objectives To examine if therapeutic hypothermia reduces the composite outcome of death, moderate or severe disability at 18 months or more after mild neonatal encephalopathy (NE).Data source MEDLINE, Cochrane database, Scopus and ISI Web of Knowledge databases, using ‘hypoxic ischaemic encephalopathy’, ‘newborn’ and ‘hypothermia’, and ‘clinical trials’ as medical subject headings and terms. Manual search of the reference lists of all eligible articles and major review articles and additional data from the corresponding authors of selected articles.Study selection Randomised and quasirandomised controlled trials comparing therapeutic hypothermia with usual care.Data extraction Safety and efficacy data extracted independently by two reviewers and analysed.Results We included the data on 117 babies with mild NE inadvertently recruited to five cooling trials (two whole-body cooling and three selective head cooling) of moderate and severe NE, in the meta-analysis. Adverse outcomes occurred in 11/56 (19.6%) of the cooled babies and 12/61 (19.7%) of the usual care babies (risk ratio 1.11 (95% CIs 0.55 to 2.25)).Conclusions Current evidence is insufficient to recommend routine therapeutic hypothermia for babies with mild encephalopathy and significant benefits or harm cannot be excluded.
Montaldo P, Ivain P, Lally P, et al., 2020, White matter injury after neonatal encephalopathy is associated with thalamic metabolite perturbations, EBioMedicine, Vol: 52, ISSN: 2352-3964
BackgroundAlthough thalamic magnetic resonance (MR) spectroscopy (MRS) accurately predicts adverse outcomes after neonatal encephalopathy, its utility in infants without MR visible deep brain nuclei injury is not known. We examined thalamic MRS metabolite perturbations in encephalopathic infants with white matter (WM) injury with or without cortical injury and its associations with adverse outcomes.MethodsWe performed a subgroup analysis of all infants recruited to the MARBLE study with isolated WM or mixed WM/cortical injury, but no visible injury to the basal ganglia/thalamus (BGT) or posterior limb of the internal capsule (PLIC). We used binary logistic regression to examine the association of MRS biomarkers with three outcomes (i) WM injury score (1 vs. 2/3); (ii) cortical injury scores (0/1 vs. 2/3); and (iii) adverse outcomes (defined as death, moderate/severe disability) at two years (yes/no). We also assessed the accuracy of MRS for predicting adverse outcome.FindingsOf the 107 infants included in the analysis, five had adverse outcome. Reduced thalamic N-acetylaspartate concentration [NAA] (odds ratio 0.4 (95% CI 0.18–0.93)) and elevated thalamic Lactate/NAA peak area ratio (odds ratio 3.37 (95% CI 1.45–7.82)) were significantly associated with higher WM injury scores, but not with cortical injury. Thalamic [NAA] (≤5.6 mmol/kg/wet weight) had the best accuracy for predicting adverse outcomes (sensitivity 1.00 (95% CI 0.16–1.00); specificity 0.95 (95% CI 0.84–0.99)).InterpretationThalamic NAA is reduced in encephalopathic infants without MR visible deep brain nuclei injury and may be a useful predictor of adverse outcomes.FundingThe National Institute for Health Research (NIHR).
Montaldo P, Lally P, Oliveira V, et al., 2019, Therapeutic hypothermia initiated within 6 hours of birth is associated with reduced brain injury on MR biomarkers in mild hypoxic ischemic encephalopathy: a non-randomised cohort study, Archives of Disease in Childhood. Fetal and Neonatal Edition, Vol: 104, Pages: F515-F520, ISSN: 1359-2998
Objective To examine the effect of therapeutic hypothermia on MR biomarkers and neurodevelopmental outcomes in babies with mild hypoxic-ischaemic encephalopathy (HIE).Design Non-randomised cohort study.Setting Eight tertiary neonatal units in the UK and the USA.Patients 47 babies with mild HIE on NICHD neurological examination performed within 6 hours after birth.Interventions Whole-body cooling for 72 hours (n=32) or usual care (n=15; of these 5 were cooled for <12 hours).Main outcome measures MRI and MR spectroscopy (MRS) within 2 weeks after birth, and a neurodevelopmental outcome assessment at 2 years.Results The baseline characteristics in both groups were similar except for lower 10 min Apgar scores (p=0.02) in the cooled babies. Despite this, the mean (SD) thalamic NAA/Cr (1.4 (0.1) vs 1.6 (0.2); p<0.001) and NAA/Cho (0.67 (0.08) vs 0.89 (0.11); p<0.001) ratios from MRS were significantly higher in the cooled group. Cooled babies had lower white matter injury scores than non-cooled babies (p=0.02). Four (27%) non-cooled babies with mild HIE developed seizures after 6 hours of age, while none of the cooled babies developed seizures (p=0.008). Neurodevelopmental outcomes at 2 years were available in 40 (85%) of the babies. Adverse outcomes were seen in 2 (14.3%) non-cooled babies, and none of the cooled babies (p=0.09).Conclusions Therapeutic hypothermia may have a neuroprotective effect in babies with mild HIE, as demonstrated by improved MRS biomarkers and reduced white matter injury on MRI. This may warrant further evaluation in adequately powered randomised controlled trials.
Montaldo P, Swamy R, Bassett P, et al., 2019, Pitfalls in using neonatal brain NAA to predict infant development - Authors' reply., The Lancet Neurology, Vol: 18, Pages: 423-424, ISSN: 1474-4422
Thayyil S, Liow N, Montaldo P, et al., 2019, Pre-emptive morphine during therapeutic hypothermia after neonatal encephalopathy: a secondary analysis, Therapeutic Hypothermia and Temperature Management, Vol: 10, Pages: 45-52, ISSN: 2153-7658
Although therapeutic hypothermia (TH) improves outcomes after neonatal encephalopathy (NE), the safety and efficacy of preemptive opioid sedation during cooling therapy is unclear. We performed a secondary analysis of the data from a large multicountry prospective observational study (Magnetic Resonance Biomarkers in Neonatal Encephalopathy [MARBLE]) to examine the association of preemptive morphine infusion during TH on brain injury and neurodevelopmental outcomes after NE. All recruited infants had 3.0 Tesla magnetic resonance imaging and spectroscopy at 1 week, and neurodevelopmental outcome assessments at 22 months. Of 223 babies recruited to the MARBLE study, the data on sedation were available from 169 babies with moderate (n = 150) or severe NE (n = 19). Although the baseline characteristics and admission status were similar, the babies who received morphine infusion (n = 141) were more hypotensive (49% vs. 25%, p = 0.02) and had a significantly longer hospital stay (12 days vs. 9 days, p = 0.009) than those who did not (n = 28). Basal ganglia/thalamic injury (score ≥1) and cortical injury (score ≥1) was seen in 34/141 (24%) and 37/141 (26%), respectively, of the morphine group and 4/28 (14%) and 3/28 (11%) of the nonmorphine group (p > 0.05). On regression modeling adjusted for potential confounders, preemptive morphine was not associated with mean (standard deviation [SD]) thalamic N-acetylaspartate (NAA) concentration (6.9 ± 0.9 vs. 6.5 ± 1.5; p = 0.97), and median (interquartile range) lactate/NAA peak area ratios (0.16 [0.12–0.21] vs. 0.13 [0.11–0.18]; p = 0.20) at 1 week, and mean (SD) Bayley-III composite motor (92 ± 23 vs. 94 ± 10; p = 0.98), language (89 ± 22 vs. 93 ±
Montaldo P, Kaforou M, Pollara G, et al., 2019, Whole blood gene expression reveals specific transcriptome changes in neonatal encephalopathy, Neonatology, Vol: 115, Pages: 68-76, ISSN: 1661-7800
BackgroundVariable responses to hypothermic neuroprotection are related to the clinical heterogeneity of encephalopathic babies, hence better disease stratification may facilitate the development of individualized neuroprotective therapies.ObjectivesWe examined if whole blood gene expression analysis can identify specific transcriptome profiles in neonatal encephalopathy. Material and MethodsWe performed next generation sequencing on whole blood RNA from twelve babies with neonatal encephalopathy, and six time-matched healthy term babies. The significantly differentially expressed genes between encephalopathic and control babies were identified. This set of genes was then compared to the host RNA response in septic neonates and subjected to pathway analysis. ResultsWe identified 950 statistically significant genes discriminating perfectly between the healthy controls and neonatal encephalopathy. The major pathways in neonatal encephalopathy were axonal guidance signaling (p =0.0009), granulocyte adhesion and diapedesis (p = 0.003), IL-12 Signaling and Production in Macrophages (p= 0.003) and hypoxia-inducible factor 1α signaling (p = 0.004). There were only 137 genes in common between neonatal encephalopathy and bacterial sepsis sets. ConclusionBabies with neonatal encephalopathy have striking differences in gene expression profiles compared with healthy control and septic babies. Gene expression profile may be useful for disease stratification based and for developing personalized neuroprotective therapies.
Lally PJ, Montaldo P, Oliveira V, et al., 2019, Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multi-centre study, Lancet Neurology, Vol: 18, Pages: 35-45, ISSN: 1474-4422
BackgroundIn neonatal encephalopathy (NE), the clinical manifestations of injury can only be reliably assessed several years after an intervention, complicating early prognostication and rendering trials of promising neuroprotectants slow and expensive. We aimed to determine the accuracy of thalamic proton magnetic resonance spectroscopy (1H MRS) biomarkers as early predictors of the neurodevelopmental abnormalities observed years after NE.MethodsWe conducted a prospective multi-centre cohort study across eight neonatal intensive care units, recruiting term neonates who received therapeutic hypothermia for NE. We obtained thalamic 1H MRS 4 to 14 days after birth, which were compared to clinical neurodevelopmental tests performed 18 to 24 months later. The primary endpoint was anabnormal outcome, defined as death, or moderate or severe disability. Receiver operating characteristic (ROC) curves were used to examine the strength of the relationship between selected biomarkers and this outcome.FindingsWe recruited 223 infants who all underwent MR imaging and spectroscopy at a median (IQR) age of 7 (5 to 10) days, with 190 (85%) followed up for neurological examination at a median (IQR) age of 23 (20 to 25) months. Of those followed up, 31 (16%) had moderate or severe disability, including one death. The thalamic concentration of Nacetylasparate, [NAA], had an area under the ROC curve (AUC) of 0·99 (95% CI 0·94 to 1·00, n=82), and lactate/NAA peak area ratio had an AUC of 0·94 (95% CI 0·89 to 0·97, n=160). From conventional MRI, abnormal signal in the posterior limb of the internal capsule (PLIC) gave an AUC of 0·82 (95% CI 0·76 to 0·87, n=190). Thalamic [NAA] was independentlyassociated with neurodevelopmental outcome scores on multivariable analysis, and had higher prognostic accuracy than conventional MR imaging (98% versus 87%; p<0·001).InterpretationThalamic 1H MRS measures acquired soon after
Montaldo P, Lally PJ, Oliveira V, et al., 2018, Hypothermic neuroprotection for neonatal encephalopathy in low-and middle-income countries: a new approach to an old problem, NeoReviews.org, Vol: 19, Pages: e735-e741, ISSN: 1526-9906
Little progress has been made over the past decade in improving the outcomes of infants with neonatal encephalopathy in low-and middle-income countries (LMICs), and millions of infants still die or sustain permanent neurodisability every year. One of the key reasons for this lack of progress is a disconnect between encephalopathy research in high-income countries and LMICs. The majority of the neonatal encephalopathy research has been conducted in high-income countries with a low disease burden, without the involvement of LMICs. Here we discuss how a collaborative approach—particularly between middle-income countries and high-income countries—enables the use of state-of-the-art magnetic resonance biomarkers and host gene expression profiling for effective disease stratification. Using the example of the Hypothermia for Encephalopathy in Low-and middle-Income countries (HELIX) trial, we describe how this approach may result in a paradigm shift in global perinatal brain research over the next decade.
Oliveira V, Martins R, Liow N, et al., 2018, Prognostic accuracy of heart rate variability analysis in neonatal encephalopathy: a systematic review, Neonatology, Vol: 115, Pages: 59-67, ISSN: 1661-7800
BACKGROUND: Heart rate variability analysis offers real-time quantification of autonomic disturbance after perinatal asphyxia, and may therefore aid in disease stratification and prognostication after neonatal encephalopathy (NE). OBJECTIVE: To systematically review the existing literature on the accuracy of early heart rate variability (HRV) to predict brain injury and adverse neurodevelopmental outcomes after NE. DESIGN/METHODS: We systematically searched the literature published between May 1947 and May 2018. We included all prospective and retrospective studies reporting HRV metrics, within the first 7 days of life in babies with NE, and its association with adverse outcomes (defined as evidence of brain injury on magnetic resonance imaging and/or abnormal neurodevelopment at ≥1 year of age). We extracted raw data wherever possible to calculate the prognostic indices with confidence intervals. RESULTS: We retrieved 379 citations, 5 of which met the criteria. One further study was excluded as it analysed an already-included cohort. The 4 studies provided data on 205 babies, 80 (39%) of whom had adverse outcomes. Prognostic accuracy was reported for 12 different HRV metrics and the area under the curve (AUC) varied between 0.79 and 0.94. The best performing metric reported in the included studies was the relative power of high-frequency band, with an AUC of 0.94. CONCLUSIONS: HRV metrics are a promising bedside tool for early prediction of brain injury and neurodevelopmental outcome in babies with NE. Due to the small number of studies available, their heterogeneity and methodological limitations, further research is needed to refine this tool so that it can be used in clinical practice.
Oliveira V, Kumutha JR E N, Somanna J, et al., 2018, Hypothermia for encephalopathy in low-income and middle-income countries: feasibility of whole-body cooling using a low-cost servo-controlled device, BMJ Paediatrics Open, Vol: 2, ISSN: 2399-9772
Although therapeutic hypothermia (TH) is the standard of care for hypoxic ischaemic encephalopathy in high-income countries, the safety and efficacy of this therapy in low-income and middle-income countries (LMICs) is unknown. We aimed to describe the feasibility of TH using a low-cost servo-controlled cooling device and the short-term outcomes of the cooled babies in LMIC. Design: We recruited babies with moderate or severe hypoxic ischaemic encephalopathy (aged <6 hours) admitted to public sector tertiary neonatal units in India over a 28-month period. We administered whole-body cooling (set core temperature 33.5°C) using a servo-controlled device for 72 hours, followed by passive rewarming. We collected the data on short-term neonatal outcomes prior to hospital discharge. Results: Eighty-two babies were included-61 (74%) had moderate and 21 (26%) had severe encephalopathy. Mean (SD) hypothermia cooling induction time was 1.7 hour (1.5) and the effective cooling time 95% (0.08). The mean (SD) hypothermia induction time was 1.7 hour (1.5 hour), core temperature during cooling was 33.4°C (0.2), rewarming rate was 0.34°C (0.16°C) per hour and the effective cooling time was 95% (8%). Twenty-five (51%) babies had gastric bleeds, 6 (12%) had pulmonary bleeds and 21 (27%) had meconium on delivery. Fifteen (18%) babies died before discharge from hospital. Heart rate more than 120 bpm during cooling (P=0.01) and gastric bleeds (P<0.001) were associated with neonatal mortality. Conclusions: The low-cost servo-controlled cooling device maintained the core temperature well within the target range. Adequately powered clinical trials are required to establish the safety and efficacy of TH in LMICs. Clinical trial registration number: NCT01760629.
Munroe PB, Addison S, Abrams DJ, et al., 2018, Postmortem genetic testing for cardiac ion channelopathies in stillbirths, Circulation: Cardiovascular Genetics, Vol: 11, ISSN: 1942-325X
BackgroundAlthough stillbirth is a significant health problem worldwide, the definitive cause of death remains elusive in many cases, despite detailed autopsy. In this study of partly explained and unexplained stillbirths, we used next-generation sequencing to examine an extended panel of 35 candidate genes known to be associated with ion channel disorders and sudden cardiac death.Methods and ResultsWe examined tissue from 242 stillbirths (≥22 weeks), including those where no definite cause of death could be confirmed after a full autopsy. We obtained high-quality DNA from 70 cases, which were then sequenced for a custom panel of 35 genes, 12 for inherited long- and short-QT syndrome genes (LQT1-LQT12 and SQT1-3), and 23 additional candidate genes derived from genome-wide association studies. We examined the functional significance of a selected variant by patch-clamp electrophysiological recording. No predicted damaging variants were identified in KCNQ1 (LQT1) or KCNH2 (LQT2). A rare putative pathogenic variant was found in KCNJ2(LQT7) in 1 case, and several novel variants of uncertain significance were observed. The KCNJ2 variant (p. R40Q), when assessed by whole-cell patch clamp, affected the function of the channel. There was no significant evidence of enrichment of rare predicted damaging variants within any of the candidate genes.ConclusionsAlthough a causative link is unclear, 1 putative pathogenic and variants of uncertain significance variant resulting in cardiac channelopathies was identified in some cases of otherwise unexplained stillbirth, and these variants may have a role in fetal demise.
Lally PJ, Montaldo P, Oliveira V, et al., 2017, Residual brain injury after early discontinuation of cooling therapy in mild neonatal encephalopathy, Archives of Disease in Childhood. Fetal and Neonatal Edition, Pages: F383-F387, ISSN: 1359-2998
We examined the brain injury and neurodevelopmental outcomes in a prospective cohort of 10 babies with mild encephalopathy who had early cessation of cooling therapy. All babies had MRI and spectroscopy within 2 weeks after birth and neurodevelopmental assessment at 2 years. Cooling was prematurely discontinued at a median age of 9 hours (IQR 5–13) due to rapid clinical improvement. Five (50%) had injury on MRI or spectroscopy, and two (20%) had an abnormal neurodevelopmental outcome at 2 years. Premature cessation of cooling therapy in babies with mild neonatal encephalopathy does not exclude residual brain injury and adverse long-term neurodevelopmental outcomes. This study refers to babies recruited into the MARBLE study (NCT01309711, pre-results stage).
Lally PJ, Montaldo P, Oliveira V, et al., 2017, Residual brain injury after early discontinuation of cooling therapy in mild neonatal encephalopathy, Archives of Disease in Childhood. Fetal and Neonatal Edition, Vol: 103, Pages: F383-F387, ISSN: 1359-2998
We examined the brain injury and neurodevelopmental outcomes in a prospective cohort of 10 babies with mild encephalopathy who had early cessation of cooling therapy. All babies had MRI and spectroscopy within 2 weeks after birth and neurodevelopmental assessment at 2 years. Cooling was prematurely discontinued at a median age of 9 hours (IQR 5-13) due to rapid clinical improvement. Five (50%) had injury on MRI or spectroscopy, and two (20%) had an abnormal neurodevelopmental outcome at 2 years. Premature cessation of cooling therapy in babies with mild neonatal encephalopathy does not exclude residual brain injury and adverse long-term neurodevelopmental outcomes. This study refers to babies recruited into the MARBLE study (NCT01309711, pre-results stage).
Oliveira V, Singhvi DP, Montaldo P, et al., 2017, Therapeutic hypothermia in mild neonatal encephalopathy: a national survey of practice in the UK, Archives of Disease in Childhood. Fetal and Neonatal Edition, Vol: 103, Pages: F388-F390, ISSN: 1359-2998
Although major cooling trials (and subsequent guidelines) excluded babies with mild encephalopathy, anecdotal evidence suggests that cooling is often offered to these infants. We report a national survey on current cooling practices for babies with mild encephalopathy in the UK. From 74 neonatal units contacted, 68 were cooling centres. We received 54 responses (79%) and included 48 (five excluded due to incomplete data and one found later not to offer cooling). Of these, 36 centres (75%) offered cooling to infants with mild encephalopathy. Although most of the participating units reported targeting 33-34°C core temperature, seven (19%) considered initiating cooling beyond 6 hours of age and 13 (36%) discontinued cooling prior to 72 hours. Babies were ventilated for cooling in two (6%) units and 13 (36%) sedated all cooled babies. Enteral feeding was withheld in 15 (42%) units and reduced below 25% of requirements in eight (22%) units. MRI and neurodevelopmental outcome evaluation were offered to all cooled babies in 29 (80%) and 27 (75%) units, respectively. Further research is necessary to ensure optimal neuroprotection in mild encephalopathy.
Thayyil S, Oliveira V, Lally PJ, et al., 2017, Hypothermia for encephalopathy in low and middle-income countries (HELIX): study protocol for a randomised controlled trial., Trials, Vol: 18, ISSN: 1745-6215
BACKGROUND: Therapeutic hypothermia reduces death and disability after moderate or severe neonatal encephalopathy in high-income countries and is used as standard therapy in these settings. However, the safety and efficacy of cooling therapy in low- and middle-income countries (LMICs), where 99% of the disease burden occurs, remains unclear. We will examine whether whole body cooling reduces death or neurodisability at 18-22 months after neonatal encephalopathy, in LMICs. METHODS: We will randomly allocate 408 term or near-term babies (aged ≤ 6 h) with moderate or severe neonatal encephalopathy admitted to public sector neonatal units in LMIC countries (India, Bangladesh or Sri Lanka), to either usual care alone or whole-body cooling with usual care. Babies allocated to the cooling arm will have core body temperature maintained at 33.5 °C using a servo-controlled cooling device for 72 h, followed by re-warming at 0.5 °C per hour. All babies will have detailed infection screening at the time of recruitment and 3 Telsa cerebral magnetic resonance imaging and spectroscopy at 1-2 weeks after birth. Our primary endpoint is death or moderate or severe disability at the age of 18 months. DISCUSSION: Upon completion, HELIX will be the largest cooling trial in neonatal encephalopathy and will provide a definitive answer regarding the safety and efficacy of cooling therapy for neonatal encephalopathy in LMICs. The trial will also provide important data about the influence of co-existent perinatal infection on the efficacy of hypothermic neuroprotection. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02387385 . Registered on 27 February 2015.
Cawley P, Few K, Greenwood R, et al., 2016, Does magnetic resonance brain scanning at 3.0 Tesla pose a hyperthermic challenge to term neonates?, The Journal of Pediatrics, Vol: 175, Pages: 228-230.e1, ISSN: 0022-3476
Next-generation 3-Tesla magnetic resonance (MR) scanners offer improved neonatal neuroimaging, but the greater associated radiofrequency radiation may increase the risk of hyperthermia. Safety data for neonatal 3-T MR scanning are lacking. We measured rectal temperatures continuously in 25 neonates undergoing 3-T brain MR imaging and observed no significant hyperthermic threat.
Montaldo P, Oliveira V, Lally PJ, et al., 2016, Therapeutic hypothermia in neonatal cervical spine injury, Archives of Disease in Childhood: Fetal & Neonatal Edition, Vol: 101, Pages: F468-F468, ISSN: 1468-2052
Montaldo P, Addison S, Oliveira V, et al., 2016, Quantification of Maceration Changes using Post Mortem MRI in Fetuses, BMC MEDICAL IMAGING, Vol: 16, ISSN: 1471-2342
BackgroundPost mortem imaging is playing an increasingly important role in perinatal autopsy, andcorrect interpretation of imaging changes is paramount. This is particularly importantfollowing intra-uterine fetal death, where there may be fetal maceration. The aim of thisstudy was to investigate whether any changes seen on a whole body fetal post mortemmagnetic resonance imaging (PMMR) correspond to maceration at conventionalautopsy.Methods: We performed pre-autopsy PMMR in 75 fetuses using a 1.5 Tesla SiemensAvanto MR scanner (Erlangen, Germany). PMMR images were reported blinded to theclinical history and autopsy data using a numerical severity scale (0 = no macerationchanges to 2 = severe maceration changes) for 6 different visceral organs (total 12).The degree of maceration at autopsy was categorized according to severity on anumerical scale (1 = no maceration to 4 = severe maceration). We also generatedquantitative maps to measure the liver and lung T2.Results: The mean PMMR maceration score correlated well with the autopsymaceration score (R2=0.93). A PMMR score of ≥ 4.5 had a sensitivity of 91%,specificity of 64%, for detecting moderate or severe maceration at autopsy. Liver andlung T2 were increased in fetuses with maceration scores of 3-4 in comparison tothose with 1-2 (liver p=0.03, lung p=0.02).Conclusions: There was a good correlation between PMMR maceration score and theextent of maceration seen at conventional autopsy. This score may be useful ininterpretation of fetal PMMR.
Lally P, PAULIAH S, MONTALDO P, et al., 2015, Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE): A Prospective Multi-Country Study, BMJ Open, Vol: 5, ISSN: 2044-6055
Despite cooling adverse outcomes are seen in upto half of the surviving infants after neonatal encephalopathy. A number of novel adjunct drug therapies with cooling have been shown to be highly neuroprotective in animal studies, and are currently awaiting clinical translation. Riggorous evaluation of these therapies in phase II trials using surrogate magnetic resonance biomarkers may speed up thier bench to bedside translation. A recent systematic review of single centres studies have suggested that Magnetic resonance spectroscopy biomarkers offers the best promise, however the prognostic accuracy of these biomarkers in cooled encephalopathic babies in a multicentre setting using different MR scan makes is not known.
Ibrahim T, Few K, Greenwood R, et al., 2015, 'Feed and wrap' or sedate and immobilise for neonatal brain MRI?, ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION, Vol: 100, Pages: F465-U95, ISSN: 1359-2998
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Soo A, Taha S, Lally P, et al., 2015, Assessment of optic nerve development using post-mortem Magnetic Resonance Imaging (MRI) in fetuses and newborns, Prenatal Diagnosis, Vol: 35, Pages: 1262-1264, ISSN: 0197-3851
What's already known about this topic?Biometric studies of fetal orbit and lens development have been shown to correlate with gestational age.No available data on optic nerve measurements in fetuses/neonates.What does this study add?Normal fetal/neonatal optic nerve diameter measurements for gestational age as measured on post‐mortem MRI scans.
Arthurs OJ, Thayyil S, Pauliah SS, et al., 2015, Diagnostic accuracy and limitations of post-mortem MRI for neurological abnormalities in fetuses and children, CLINICAL RADIOLOGY, Vol: 70, Pages: 872-880, ISSN: 0009-9260
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- Citations: 65
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