Monitorização neurológica por meio do eletroencefalograma de amplitude integrada na unidade de terapia intensiva neonatal: uma revisão integrativa de literatura / Neurological monitoring through electroencephalogram integrated in the neonatal intensive care unit: an integrative literature review

Introdução: As proporções relativamente elevadas de comprometimentos neurológicos em recém-nascidos admitidos nas Unidades de Terapia Intensiva Neonatal (UTIN) advém principalmente de convulsões, situações de difícil diagnóstico dentro da neuropediatria, visto que nos neonatos, muitas vezes, podem ser evidenciadas apenas por distúrbios eletrográficos. Além disso, alguns movimentos paroxísticos podem ser tratados erroneamente como convulsões, culminando em iatrogenias. Com isso, o uso do eletroencefalograma de amplitude integrada (aEEG), constitui-se como uma ferramenta compacta e inovadora que pode ser utilizada para auxiliar o diagnóstico de convulsões na UTIN. Justificativa: Conhecer os principais aspectos relacionados à implementação do aEEG nas UTINs, torna-se relevante de forma a contribuir para o entendimento dos benefícios e limitações do instrumento. Objetivos: Buscar evidências na literatura sobre o valor preditivo do aEEG e o seu impacto no prognóstico neurológico de recém-nascidos enfermos, bem como identificar potenciais benefícios em relação ao EEG convencional e agregar conhecimento aos debates empenhados nos escritos nacionais. Metodologia: Trata-se de um estudo integrativo revisional de literatura, utilizando as bases Biblioteca Virtual de Saúde (BVS), EbscoHost, National Library of Medicine (PubMed MEDLINE) e Scientific Eletronic Library Online (SCIELO). Resultados: Embora possua sensibilidade e especificidade variáveis, o aEEG tem bom valor preditivo e possibilita a identificação de convulsões subclínicas e de forma precoce, bem como a redução de sobretratamento e iatrogenias. Conclusão: O aEEG é mais simples e compacto que o EEG convencional, possui bom valor preditivo e auxilia no diagnóstico de convulsões neonatais e na redução do sobretratamento.  

“EPINEO” Monocentric Retrospective Study on Neonatal Seizures: Incidence, ILAE Seizure Type, Epileptic Syndrome, EEG and Etiology

Purpose: In the last decade important updates have occurred in the management of neonatal seizures (NS) that may have changed NS epidemiology. The International League Against Epilepsy (ILAE) has published a new classification for neonatal seizures. The aim of our study was to determine the current incidence of NS and the correlation between ILAE seizure type, epileptic syndrome, EEG and etiology. Materials and methods: This is a retrospective single-center cohort study on consecutive neonates with neurophysiological confirmation of NS from 2009 to 2022 performed in a tertiary neonatal center. Clinical information including medical history, neurological examination, EEG/aEEG, neuroimaging, laboratory tests were inserted on a specifically designed Redcap database. Seizure type and epileptic syndromes were classified according to the new ILAE classification andEEG/aEEG with INNESCO score. Results and conclusions: 145 neonates presented with NS: 101 term (69.7%) and 44 preterm (30.3). Incidence in the overall population at our center was 1.59/1000, in the inborn population 1.11/1000, increasing with earlier gestational age up to 17 times. In comparison with previous studies, we found a reduction in HIE-related NS and a higher contribution of genetic etiology to NS mediated by different mechanisms: functional epilepsy, metabolic epilepsy, structural epilepsy and acute provoked seizures (metabolic or vascular etiology) having a genetic etiology as primary cause triggering the cascade of events finally leading to seizures. Our study confirms the usefulness of the new ILAE classification for neonates to address etiology, confirming the association previously found between seizure type and etiology. A problematic issue is represented by the high risk of inter-operator variability regarding the use of the “sequential seizure” term. Specific types of sequential seizures with tonic-onset or tonic-clonic sequence patterns, often with alternating side onset within the same seizure or different seizures, are highly related to epileptic channelopathies

Precision Medicine in Neonates: A Tailored Approach to Neonatal Brain Injury

Despite advances in neonatal care to prevent neonatal brain injury and neurodevelopmental impairment, predicting long-term outcome in neonates at risk for brain injury remains difficult. Early prognosis is currently based on cranial ultrasound (CUS), MRI, EEG, NIRS, and/or general movements assessed at specific ages, and predicting outcome in an individual (precision medicine) is not yet possible. New algorithms based on large databases and machine learning applied to clinical, neuromonitoring, and neuroimaging data and genetic analysis and assays measuring multiple biomarkers (omics) can fulfill the needs of modern neonatology. A synergy of all these techniques and the use of automatic quantitative analysis might give clinicians the possibility to provide patient-targeted decision-making for individualized diagnosis, therapy, and outcome prediction. This review will first focus on common neonatal neurological diseases, associated risk factors, and most common treatments. After that, we will discuss how precision medicine and machine learning (ML) approaches could change the future of prediction and prognosis in this field

Early prediction of hypoxic ischaemic encephalopathy in newborn infants in a resource-limited setting

Includes bibliographical references.Hypoxic ischaemic encephalopathy (HIE) after birth is an important cause of neonatal morbidity and mortality, particularly in resource-limited regions. Therapeutic hypothermia initiated within the first 6 hours of life, in settings that can offer neonatal intensive care, is a therapy that can reduce death or severe disability in newborn infants with moderate or severe HIE. Therapeutic hypothermia has not been shown to be safe or effective in low-resource settings where neonatal intensive care is not available; however, there are situations such as in some centres in South Africa, where limited neonatal intensive care (NICU) is available against a background of moderate neonatal mortality rates, relatively low socio-economic conditions and limited capacity for long-term follow-up. In such settings, accurate case definition and early prediction of HIE and outcome may assist with the appropriate allocation of resources. The amplitude-integrated electro-encephalogram (aEEG) is an ideal tool to use for prediction of outcome and the need for cooling, but it’s availability is limited, particularly at primary and secondary hospitals

Predicting death or long-term neurodevelopmental outcome in term newborns after hypoxic ischemic encephalopathy

Hypoxic-ischemic encephalopathy after perinatal asphyxia is a severe neonatal disease with a high mortality and morbidity rate despite recent improvements in medical care in the Neonatal Intensive Care Unit. In the diagnostic and prognostic workup of these patients, a wide range of biochemical, neurophysiological and radiological tests is performed. Although many of these predictive parameters have been studied, an internationally accepted, validated prediction model to predict the long-term neurodevelopmental outcome in this high-risk population is currently lacking. This thesis aimed to investigate and contribute to the current evidence on long-term outcome prediction of newborns with hypoxic ischemic encephalopathy treated with controlled therapeutic hypothermia. The systematic review performed confirmed that to date there is no clinically applicable multivariate prediction model available for long-term outcome in these infants. The additional studies showed that the MRI Weeke score is a reliable predictor of outcome and should be implemented in clinical practice. It was demonstrated that multiple organ dysfunction should not be taken into account when predicting or discussing the outcome of these infants. Neither the presence of seizures, nor the severity of seizures (described by the number of anti-epileptic drugs needed) are associated with the combined outcome up until the age of five years after correction for important confounders. Finally, a novel prediction model for the combined outcome death or NDI at two years of age was build and internally validated

Multimodal characterisation of the infant response to retinopathy of prematurity screening and treatment

Retinopathy of prematurity (ROP) is a condition which affects premature infants and is a cause of childhood blindness. Screening is performed repeatedly during the preterm period, using binocular indirect ophthalmoscopy (BIO), to identify disease at a treatable stage; unfortunately screening and treatment are considered to be painful and stressful for infants. Pain and stress during the preterm period can lead to negative consequences for infant development. Reduction of pain and stress during ROP procedures has therefore been attempted using pharmacological and non-pharmacological strategies. However, it is challenging to evaluate the effectiveness of such interventions due to limitations in the accurate measurement of infant pain and stress. In this thesis, novel approaches to quantifying infant pain and stress evoked by ROP procedures are presented. Infant brain activity was characterised using quantitative electroencephalography (EEG) analysis to test the hypothesis that ROP screening evokes noxious-related changes in infant brain activity. The results of this study suggest BIO ROP screening evokes a significant increase in higher frequency brain activity (12 - 30 Hz), and that increase in relative beta power may be a measure of nociception in preterm infants. Infant cardiac autonomic reactivity was characterised using heart rate variability (HRV) analysis to test the hypothesis that ROP screening evokes stress-related autonomic changes. The results of this study suggest BIO ROP screening evokes significant reduction in HRV measures of parasympathetic nervous system activity, indicating a physiological stress response in preterm infants. An approach to characterising the infant response to non-contact ultra-widefield photography (Optos screening) and ROP treatment was also demonstrated. Recruitment of subjects was curtailed by the outbreak of COVID-19, therefore the investigations are presented as an example of approaches which could be performed in a larger sample size. In summary, the research described in this thesis aims to contribute to understanding of the infant experience of ROP procedures; to characterise changes in noxious-related brain activity and stress-related cardiac reactivity evoked by BIO ROP screening, and to use these measures to investigate the infant response to an alternative screening method and to ROP treatments. Improved understanding of the infant experience of ROP screening and treatment may allow clinicians to better identify and treat infant pain and stress during essential clinical procedures

Whole-body hypothermia in mild neonatal encephalopathy: protocol for a multicentre phase III randomised controlled trial

Background: Mild hypoxic ischemic encephalopathy is associated with sub optimal cognition and learning difficulties at school age. Although whole-body hypothermia reduces death and disability after moderate or severe encephalopathy in high-income countries, the safety and efficacy of hypothermia in mild encephalopathy is not known. The cooling in mild encephalopathy (COMET) trial will examine if whole-body hypothermia improves cognitive development of neonates with mild encephalopathy. Methods: The COMET trial is a phase III multicentre open label two-arm randomised controlled trial with masked outcome assessments. A total of 426 neonates with mild encephalopathy will be recruited from 50 to 60 NHS hospitals over 2 ½ years following parental consent. The neonates will be randomised to 72 h of whole-body hypothermia (33.5 ± 0.5 C) or normothermia (37.0 ± 0.5 C) within six hours or age. Prior to the recruitment front line clinical staff will be trained and certified on expanded modified Sarnat staging for encephalopathy. The neurological assessment of all screened and recruited cases will be video recorded and centrally assessed for quality assurance. If recruitment occurs at a non-cooling centre, neonates in both arms will be transferred to a cooling centre for continued care, after randomisation. All neonates will have continuous amplitude integrated electroencephalography (aEEG) at least for the first 48 h to monitor for seizures. Predefined safety outcomes will be documented, and data collected to assess resource utilization of health care. A central team masked to trial group allocation will assess neurodevelopmental outcomes at 2 years of age. The primary outcome is mean difference in composite cognitive scores on Bayley scales of Infant and Toddler development 4th Edition. Discussion: The COMET trial will establish the safety and efficacy of whole-body hypothermia for mild hypoxic ischaemic encephalopathy and inform national and international guidelines in high income countries. It will also provide an economic assessment of whole-body hypothermia therapy for mild encephalopathy in the NHS on cost-effectiveness grounds. Trial registration number: NCT05889507 June 5, 2023

Long-term outcome after hypothermia-treated hypoxic-ischaemic encephalopathy

Hypoxic-ischaemic encephalopathy (HIE) is a major cause of acquired brain injury in newborn infants. It is a potentially life-threatening condition that leaves survivors at substantial risk of life-long debilitating sequelae including cerebral palsy, epilepsy, intellectual disability, sensory disruption, behavioural issues, executive difficulties and autism spectrum disorder. More subtle cognitive impairments are common among survivors free of major neuromotor disability. Therapeutic hypothermia (TH) reduces the risk of death and disability in nearterm/term new-born infants with moderate and severe HIE. Outcomes in adolescence and adulthood following HIE treated with TH are not yet known. The majority of infants with HIE also suffer multi-organ dysfunction resulting from the hypoxic-ischaemic insult. The kidneys are particularly sensitive to hypoxia-ischaemia, with up to 72% of asphyxiated infants suffering acute kidney injury (AKI) prior to the advent of TH. Evidence point to AKI being independently associated with increased neonatal morbidity and mortality. To date, very little is known about long-term renal consequences following neonatal AKI in asphyxiated infants treated with TH. The overall aim of this thesis was to contribute to the improved treatment and care of infants with HIE by means of increased knowledge about the predictive value of early aEEG, neonatal AKI, and long-term outcomes in the era of TH. In a small population-based cohort, the predictive value of early amplitude-integrated EEG (aEEG) was demonstrated to be altered in infants treated with TH due to HIE. Poor outcome at the age of 1 year was only seen among infants with a persisting abnormal aEEG background pattern at and beyond 24 hours of age. In a population-based, prospective, longitudinal study including all children treated with TH between 2007 and 2009 in Stockholm, Sweden, we assessed neuromotor, neurologic, cognitive and behavioural outcomes at 6-8 and 10-12 years of age. Seventeen per cent of survivors developed CP. Survivors free of major neuromotor impairment had cognitive abilities within normal range. Repeated assessment in early adolescence revealed new deficits in 26% of children with previously favourable outcome. The proportion of children with executive difficulties in this patient population appears to be higher than in the general population. Outcomes in children with a history of moderate HIE remain heterogenous also in the era of TH. In a population-based cohort of all children treated with TH between 2007 and 2009 in Stockholm, Sweden, 45% suffered neonatal AKI. Severe AKI necessitating kidney support therapy was rare. Among infants with AKI, 20% fulfilled only the urinary output criterion of the neonatal modified KDIGO (Kidney Disease Improving Global Outcomes) definition. Mortality was higher among infants with AKI. At 10-12 years of age, 21% of children had decreased glomerular filtration rate (GFR) estimated from creatinine with the Schwartz-Lyon equation. A more in-depth assessment of renal functions in the above-mentioned population-based cohort demonstrated that renal sequelae (defined as decreased GFR, albuminuria, hypertension or normal high blood pressure, reduced renal volume on magnetic resonance imaging, or elevated Fibroblast Growth Factor 23) were rare at 10-12 years of age following perinatal asphyxia and TH. The Schwarz-Lyon equation appears to underestimate GFR in this patient population