Prognostic value of neonatal EEG following therapeutic hypothermia in survivors of hypoxic-ischemic encephalopathy

Objective: Early prediction of neurological deficits following neonatal hypoxic-ischemic encephalopathy (HIE) may help to target support. Neonatal animal models suggest that recovery following hypoxia-ischemia depends upon cortical bursting. To test whether this holds in human neonates, we correlated the magnitude of cortical bursting during recovery (≥postnatal day 3) with neurodevelopmental outcomes. Methods: We identified 41 surviving infants who received therapeutic hypothermia for HIE (classification at hospital discharge: 19 mild, 18 moderate, 4 severe) and had 9-channel electroencephalography (EEG) recordings as part of their routine care. We correlated burst power with Bayley-III cognitive, motor and language scores at median 24 months. To examine whether EEG offered additional prognostic information, we controlled for structural MRI findings. Results: Higher power of central and occipital cortical bursts predicted worse cognitive and language outcomes, and higher power of central cortical bursts predicted worse motor outcome, all independently of structural MRI findings. Conclusions: Clinical EEG after postnatal day 3 may provide additional prognostic information by indexing persistent active mechanisms that either support recovery or exacerbate brain damage, especially in infants with less severe encephalopathy. Significance: These findings could allow for the effect of clinical interventions in the neonatal period to be studied instantaneously in the future

The role of transcranial grayscale and Doppler ultrasound examination in diagnosis of neonatal hypoxic-ischemic encephalopathy

Background: The role of transcranial grayscale ultrasound (TC-GSUS) and transcranial color Doppler (TCD) in the diagnosis and prognosis of neonatal hypoxic-ischemic encephalopathy (HIE) is still questionable.Objective: This study targeted to evaluate the role of TC-GSUS and TCD in diagnosis and prediction of the outcome of neonates with suspected HIE in comparison to Sarnat's clinical scoring.Patients and methods: 26 neonates with suspected HIE were clinically evaluated and the severity of HIE was categorized according to Sarnat's clinical staging. Then, all neonates underwent sonographic examinations. TC-GSUS was performed at levels of anterior, mastoid, and posterior fontanelles and the level of the temporal window.Results: Cranial biometry had negative and positive rates for HIE of 7.7% and 92.3%, respectively. Using TC-GSUS, periventricular leukomalacia, intraventricular hemorrhage, brain edema, and hydrocephalus were detected in 17, 19, 14, and 16 patients, respectively. According to the resistive index (RI) of intracranial vessels, TCD excluded HIE in 11 patients and assured diagnosis of HIE with varying severity in 15 patients. Five neonates died and four developed neurological affection during follow-up. The outcome was correlated with Sarnat’s scoring, ventricular-hemispheric ratio, and abnormalities of RI. Statistical analyses defined severity of HIE as judged by RI as the significant predictor for mortality and abnormal RI of anterior cerebral (ACA) and internal carotid arteries (ICA) are the most significant predictors of outcomes.Conclusion: TCD can diagnose HIE in neonates with high sensitivity and specificity and abnormal RI of ICA and ACA might be used as valuable diagnostic and prognostic tests

Automated EEG background analysis to identify neonates with hypoxic-ischemic encephalopathy treated with hypothermia at risk for adverse outcome: A pilot study

Background: To improve the objective assessment of continuous video-EEG (cEEG) monitoring of neonatal brain function, the aim was to relate automated derived amplitude and duration parameters of the suppressed periods in the EEG background (dynamic Interburst Interval= dIBIs) after neonatal hypoxic-ischemic encephalopathy (HIE) to favourable or adverse neurodevelopmental outcome. Methods: Nineteen neonates (gestational age 36-41 weeks) with HIE underwent therapeutic hypothermia and had cEEG-monitoring. EEGs were retrospectively analyzed with a previously developed algorithm to detect the dynamic Interburst Intervals. Median duration and amplitude of the dIBIs were calculated at 1h-intervals. Sensitivity and specificity of automated EEG background grading for favorable and adverse outcomes were assessed at 6h-intervals. Results: Dynamic IBI values reached the best prognostic value between 18 and 24h (AUC of 0.93). EEGs with dIBI amplitude ≥15 μV and duration 10s were specific for adverse outcome (89-100%) at 18-24h (n = 10). Extremely low voltage and invariant EEG patterns were indicative of adverse outcome at all time points. Conclusions: Automated analysis of the suppressed periods in EEG of neonates with HIE undergoing TH provides objective and early prognostic information. This objective tool can be used in a multimodal strategy for outcome assessment. Implementation of this method can facilitate clinical practice, improve risk stratification and aid therapeutic decision-making. A multicenter trial with a quantifiable outcome measure is warranted to confirm the predictive value of this method in a more heterogeneous dataset

Memory deficits following neonatal critical illness: A common neurodevelopmental pathway

Summary Over the last decade, knowledge has emerged that children growing up after neonatal critical illness, irrespective of underlying diagnosis, are at risk of memory impairment and school problems. Strikingly, these problems are manifest even when intelligence is normal. In this review, we propose a common neurodevelopmental pathway following neonatal critical illness by demonstrating that the survivors of preterm birth, congenital heart disease, and severe respiratory failure, share an increased risk of long-term memory deficits and associated hippocampal alterations. Rather than being a consequence of underlying diagnosis, we suggest that this shared vulnerability is most likely related to common conditions associated with neonatal critical illness. These include hypoxia, neuroinflammation, stress, exposure to anaesthetics, or a complex interplay of these factors at different postconceptional ages. Future work should be aimed at improving early identification of patients at risk and evaluating intervention modalities, such as cognitive or exercise training

Ability of early neurological assessment and continuous EEG to predict long term neurodevelopmental outcome at 5 years in infants following hypoxic-ischaemic encephalopathy

Hypoxic-ischaemic encephalopathy (HIE) symptoms evolve during the first days of life and their monitoring is critical for treatment decisions and long-term outcome predictions. This thesis aims to report the five-year outcome of a HIE cohort born in the pre-therapeutic hypothermia era and to evaluate the predictive value of (a) neonatal neurological and EEG markers and (b) development in the first 24 months, for outcome. Methods: Participants were recruited at age five from two birth cohorts; HIE and Comparison. Repeated neonatal neurological assessments using the Amiel-TisonNeurological-Assessment-at-Term, continuous video EEG monitoring in the first 72 hours, and Sarnat grading at 24 hours were recorded. EEG severity grades were assigned at 6, 12 and 24 hours. Development was assessed in the HIE cohort at 6, 12 and 24 months using the Griffiths Mental Development (0-2) Revised Scales. At age five, intellectual (WPPSI-IIIUK scale), neuropsychological (NEPSY-II scales), neurological and ophthalmic testing was completed. Results: 5-year outcomes were available for 81.5% (n=53) of HIE and 71.4% (n=30) of Comparison cohorts. In HIE, 47.2% (27% mild, 47% moderate, 83% severe Sarnat), had non-intact outcome vs. 3.3% of the Comparison cohort. Non-intact outcome rates by 6-hour EEG-grade were: grade0=3%, grade1=25%, grade2=54%, grade3/4=79%. In HIE, processing speed (p=0.01) and verbal short-term memory (p=0.005) were below test norms. No significant differences were found in IQ, NEPSY-II or ocular biometry scores between children following mild and moderate HIE. Median IQ scores for mild (99(94-112),p=grade 2) at 24hours had superior positive predictive value (74%; AUROC(95%CI)=0.70(0.55-0.85) for non-intact 5-year outcome than abnormal EEG at 6 hours (68%; AUROC(95%CI)=0.71(0.56-0.87). Within-child development scores were inconsistent across the first 24 months. Although all children with intact 24-month Griffiths quotient (n=30) had intact 5-year IQ, 8/30 had non-intact overall outcome. Conclusion: Predictive value of neonatal neurological assessments and an EEG grading system for outcome was confirmed. Intact early childhood outcomes post-HIE may mask subtle adverse neuropsychological sequelae into the school years. This thesis supports emerging evidence that mild-grade HIE is not a benign condition and its inclusion in studies of neuroprotective treatments for HIE is warranted

Diffusion tensor imaging and resting state functional connectivity as advanced imaging biomarkers of outcome in infants with hypoxic-ischaemic encephalopathy treated with hypothermia

Therapeutic hypothermia confers significant benefit in term neonates with hypoxic-ischaemic encephalopathy (HIE). However, despite the treatment nearly half of the infants develop an unfavourable outcome. Intensive bench-based and early phase clinical research is focused on identifying treatments that augment hypothermic neuroprotection. Qualified biomarkers are required to test these promising therapies efficiently. This thesis aims to assess advanced magnetic resonance imaging (MRI) techniques, including diffusion tensor imaging (DTI) and resting state functional MRI (fMRI) as imaging biomarkers of outcome in infants with HIE who underwent hypothermic neuroprotection. FA values in the white matter (WM), obtained in the neonatal period and assessed by tract-based spatial statistics (TBSS), correlated with subsequent developmental quotient (DQ). However, TBSS is not suitable to study grey matter (GM), which is the primary site of injury following an acute hypoxic-ischaemic event. Therefore, a neonatal atlas-based automated tissue labelling approach was applied to segment central and cortical grey and whole brain WM. Mean diffusivity (MD) in GM structures, obtained in the neonatal period correlated with subsequent DQ. Although the central GM is the primary site of injury on conventional MRI following HIE; FA within WM tissue labels also correlated to neurodevelopmental performance scores. As DTI does not provide information on functional consequences of brain injury functional sequel of HIE was studied with resting state fMRI. Diminished functional connectivity was demonstrated in infants who suffered HIE, which associated with an unfavourable outcome. The results of this thesis suggest that MD in GM tissue labels and FA either determined within WM tissue labels or analysed with TBSS correlate to subsequent neurodevelopmental performance scores in infants who suffered HIE treated with hypothermia and may be applied as imaging biomarkers of outcome in this population. Although functional connectivity was diminished in infants with HIE, resting state fMRI needs further study to assess its utility as an imaging biomarker following a hypoxic-ischaemic brain injury.Open Acces

Heart rate variability during periods of low blood pressure as a predictor of short-term outcome in preterms

Efficient management of low blood pressure (BP) in preterm neonates remains challenging with a considerable variability in clinical practice. The ability to assess preterm wellbeing during episodes of low BP will help to decide when and whether hypotension treatment should be initiated. This work aims to investigate the relationship between heart rate variability (HRV), BP and the short-term neurological outcome in preterm infants less than 32 weeks gestational age (GA). The predictive power of common HRV features with respect to the outcome is assessed and shown to improve when HRV is observed during episodes of low mean arterial pressure (MAP) - with a single best feature leading to an AUC of 0.87. Combining multiple features with a boosted decision tree classifier achieves an AUC of 0.97. The work presents a promising step towards the use of multimodal data in building an objective decision support tool for clinical prediction of short-term outcome in preterms who suffer episodes of low BP