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

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

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

Early diagnosis and early intervention in cerebral palsy

This paper reviews the opportunities and challenges for early diagnosis and early intervention in cerebral palsy (CP). CP describes a group of disorders of the development of movement and posture, causing activity limitation, that are attributed to disturbances that occurred in the fetal or infant brain. Therefore the paper starts with a summary of relevant information from developmental neuroscience. Most lesions underlying CP occur in the second half of gestation, when developmental activity in the brain reaches its summit. Variations in timing of the damage not only result in different lesions, but also in different neuroplastic reactions and different associated neuropathologies. This turns CP into a heterogeneous entity. This may mean that the best early diagnostics and the best intervention methods may differ for various subgroups of children with CP. Next, the paper addresses possibilities for early diagnosis. It discusses the predictive value of neuromotor and neurological exams, neuro-imaging techniques and neurophysiological assessments. Prediction is best when complementary techniques are used in longitudinal series. Possibilities for early prediction of CP differ for infants admitted to neonatal intensive care and other infants. In the former group best prediction is achieved with the combination of neuro-imaging and the assessment of general movements, in the latter group best prediction is based on carefully documented milestones and neurological assessment. The last part reviews early intervention in infants developing CP. Most knowledge on early intervention is based on studies in high risk infants without CP. In these infants early intervention programs promote cognitive development until preschool age; motor development profits less. The few studies on early intervention in infants developing CP suggest that programs that stimulate all aspects of infant development by means of family coaching are most promising. More research is urgently neede

Neurodevelopmental outcome of the high risk infant in Cape Town

The outcome of high risk infants provides an important audit of neonatal care. This audit renders valuable information to clinicians, parents and health care planners. Available outcome data from the developing world are sparse and urgently needed. This work was compiled with three aims in mind: to provide data from Cape Town on outcome of high risk infants (including both infants of very low birthweight and infants who have survived hypoxic ischaemic encephalopathy); to evaluate selected early neurodevelopmental assessments of these infants; and to propose a protocol for their effective follow-up. Three separate cohorts were selected and studied in order to achieve these aims. A prospective six-year follow-up study of infants with birth weights less than 1250 g was undertaken at Groote Schuur Hospital's Neonatal Intensive Care Unit. The aim of the study was to document the morbidity, mortality and neurodevelopmental outcome of these infants. Of 235 liveborn infants, 143 (61 %) survived to discharge. Better survival was documented for infants who weighed more than 900 g and were over 30 weeks gestation and whose mothers attended antenatal care. One hundred and six infants (83% of survivors) underwent clinical assessment at one year of age and were evaluated with the Griffiths Scales of Mental Development. Ninety six (91 %) of these survivors were seen and tested at two years of age and 80 (76%) were seen at six years of age together with 70 matched controls who had normal birthweights. Of the 106 infants assessed at one year of age, six infants were diagnosed as cerebral palsied, six were globally developmentally delayed without signs of cerebral palsy and one infant showed significant motor delay with a normal developmental quotient. At two years of age one further infant had cerebral palsy and nine more infants were developmentally delayed. At six years of age five infants had cerebral palsy, one was intellectually disabled and three were intellectually borderline. The major disability rate at one year of age was 11%, at two years of age was 22% and at six years of age was eight percent. The incidence of low birthweight children with possible learning disability was three times that of their matched controls and overall, the low birthweight children scored significantly less in all developmental measures. Forty-five infants who developed hypoxic ischaemic encephalopathy after birth were studied prospectively. A numeric scoring system for the assessment of hypoxic ischaemic encephalopathy during the neonatal period which had previously been developed at Groote Schuur Hospital was tested. The value of the score in predicting neurodevelopmental outcome at one year of age was assessed. Thirty five infants were evaluated at 12 months of age by full neurological examination and the Griffiths Scales of Mental Development. Five infants were assessed at an earlier stage, 4 who died before 6 months of age and one infant who was hospitalised at the time of the 12-month assessment. Twenty three (58%) of the infants were normal, 17 (42%) were abnormal, 16 with cerebral palsy and one with developmental delay. 25 infants were re-evaluated at 3 years of age. 15 of these 25 had been normal at one year of age and were evaluated with ten controls who had had an uneventful perinatal course. The Hypoxic lschaemic Encephalopathy Score was highly predictive for outcome. The best correlation with outcome was a combination of the peak score and evaluation on day seven; giving a positive predictive value of 92% and a negative predictive value of 100% for abnormal outcome, with a sensitivity of 100% and specificity of 93%. At three years of age the HIE survivors without cerebral palsy scored as well as their matched controls on Griffiths developmental evaluation. In these normal survivors no correlation between severity of HIE and developmental quotient was demonstrated. Infants with neurodevelopmental abnormality need to start therapy early and because of this, should be detected as soon as possible. Currently, no widely accepted method of early evaluation exists. A Perinatal Risk Rating, the Dubowitz Neurological Assessment and the Infant Neuromotor Assessment were compared in terms of predicting neurodevelopmental outcome at one year of age. A cohort of 130 consecutive neonatal intensive care unit graduates were selected according to high risk criteria. Each infant was examined at term gestational age on the Dubowitz Neurological Assessment and a Perinatal Risk Rating was allocated. The study infants were seen again at 18 weeks corrected age, when an Infant Neuromotor Assessment was done, and at one year of age the Griffiths Scales of Mental Developmental and full neurological examination were carried out. Of the 130 infants assessed at term, all were seen at 18 weeks. Thereafter five were lost to follow-up and two died. The outcome of all the remaining 123 infants is known. Prediction of a normal outcome at 1 year of age on the Dubowitz Neurological Assessment was 96% and for the Perinatal Risk Rating, 98%, but for an abnormal outcome they predicted only 56% and 42% respectively. The Infant Neurological Assessment at 18 weeks of age predicted a normal outcome at one year in 99% and an abnormal outcome in 82%. Very low birthweight infants are at higher risk for cerebral palsy and intellectual disability. In Groote Schuur Hospital, at six years of age, the major disability rate for infants with birthweights less than 1250 g was eight percent. Forty percent of term infants who survived hypoxic ischaemic encephalopathy had cerebral palsy with associated intellectual disability. The use of the Perinatal Risk Rating is appropriate in newborn facilities where cranial ultrasound is available. Otherwise the Dubowitz Neurological Assessment is an appropriate screening tool in the newborn period. Use of the Hypoxic Ischaemic Encephalopathy Score is recommended for clinical evaluation, prognostication and risk rating. It is proposed that high risk infants should be evaluated at 18 weeks corrected age with the Infant Neuromotor Assessment at a tertiary centre. If this assessment is normal, the infant can then be discharged to community clinic follow-up. Infants with more than one deviant sign at this age need continued review and those with more than three signs should be referred for neurodevelopmental therapy to a comprehensive neurodevelopmental clinic. Even those high-risk infants whose assessments are normal should be enrolled in a pre-school centre at five years of age to facilitate detection of learning problems prior to school entry

Early Diagnostics and Early Intervention in Neurodevelopmental Disorders-Age-Dependent Challenges and Opportunities

This review discusses early diagnostics and early intervention in developmental disorders in the light of brain development. The best instruments for early detection of cerebral palsy (CP) with or without intellectual disability are neonatal magnetic resonance imaging, general movements assessment at 2-4 months and from 2-4 months onwards, the Hammersmith Infant Neurological Examination and Standardized Infant NeuroDevelopmental Assessment. Early detection of autism spectrum disorders (ASD) is difficult; its first signs emerge at the end of the first year. Prediction with the Modified Checklist for Autism in Toddlers and Infant Toddler Checklist is possible to some extent and improves during the second year, especially in children at familial risk of ASD. Thus, prediction improves substantially when transient brain structures have been replaced by permanent circuitries. At around 3 months the cortical subplate has dissolved in primary motor and sensory cortices; around 12 months the cortical subplate in prefrontal and parieto-temporal cortices and cerebellar external granular layer have disappeared. This review stresses that families are pivotal in early intervention. It summarizes evidence on the effectiveness of early intervention in medically fragile neonates, infants at low to moderate risk, infants with or at high risk of CP and with or at high risk of ASD

Infants on the move: bibliometric analyses of observational vs. digital means of screening infant development

Neurodevelopmental disorders are on the rise, yet their average diagnosis is after 4.5 years old. This delay is partly due to reliance on social-communication criteria, which require longer maturation than scaffolding elements of neuromotor control. Much earlier criteria could include reflexes, monitoring of the quality of spontaneous movements from central pattern generators and maturation of intentional movements and their overall sensation. General Movement Assessment (GMA) studies these features using observational means, but the last two decades have seen a surge in digital tools that enable non-invasive, continuous tracking of infants’ spontaneous movements. Despite their importance, these tools are not yet broadly used. In this work, using CiteSpace, VOSViewer and SciMAT software, we investigate the evolution of the literature on GMA and the methods in use today, to estimate how digital techniques are being adopted. To that end, we created maps of key word co-occurrence networks, co-author networks, document co-citation analysis and strategic diagrams of 295 publications based on a search in the Web of Science, Dimensions and SCOPUS databases for: ‘general movement assessment’ OR ‘general movements assessment’. The nodes on the maps were categorized by size, cluster groups and year of publication. We found that the state-of-the-art methodology to diagnose neurodevelopmental disorders still relies heavily on observation. Several groups in classical GMA research have branched out to incorporate new techniques, but few groups have adopted digital means. We report on additional analyses of methods and biosensors usage and propose that combining traditional clinical observation criteria with digital means may allow earlier diagnoses and interventional therapies for infants