P A Hamilton

Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy.

ABSTRACT: To investigate the prognostic significance of abnormalities of oxidative phosphorylation, the brains of 61 newborn infants born at 27-42 wk of gestation and suspected of hypoxic-ischemic brain injury were examined by surface-coil phosphorus magnetic resonance spectroscopy. Of these infants, 23 died, and the neurodevelopmental status of the 38 survivors was assessed at 1 y of age. Of the 28 infants whose phosphocreatine/inorganic orthophosphate (PCr/Pi) ratios fell below 95% confidence limits for normal infants, 19 died, and of the nine survivors, seven had serious multiple impairments (sensitivity 74%, specificity 92%, positive predictive value for unfavorable outcome 93%). Of the 12 infants with ATP/total phosphorus ratios below 95% confidence limits 11 died (sensitivity 47%, specificity 97%, positive predictive value 91%). Among the 46 infants with increased cerebral echodensities, PCr/Pi was more likely to be low, and prognosis poor, in infants whose echodensities were diffuse or indicated intraparenchymal hemorrhage than in infants whose echodensities were consistent with periventricular leukomalacia. We conclude that when reduced values for PCr/Pi indicating severely impaired oxidative phosphorylation are found in the brains of infants suspected of hypoxicischemic injury, the prognosis for survival without serious multiple impairments is very poor, and that when ATP/ total phosphorus is reduced, death is almost inevitable.

CEREBRAL ENERGY METABOLISM STUDIED WITH PHOSPHORUS NMR SPECTROSCOPY IN NORMAL AND BIRTH-ASPHYXIATED INFANTS

Phosphorus (31P) nuclear magnetic resonance spectroscopy was used to study intracellular metabolism in the brains of 6 normal newborn infants and 10 infants who had been asphyxiated during delivery. In the normal infants spectral peaks mainly attributable to adenosine triphosphate, phosphocreatine (PCr), phosphodiesters plus phospholipids, and inorganic orthophosphate (Pi) were always detected, together with an additional large peak in the phosphomonoester region indicating the presence of a metabolite or metabolites (probably largely phosphoethanolamine) which may be involved in rapid growth of the brain. In the asphyxiated infants, data obtained on the first day of life showed no differences from those in normal infants, but by the second to ninth days inverse changes in the concentrations of PCr and Pi had caused a significant reduction in PCr/Pi. This latency suggest the possibility of effective early treatment before irreversible metabolic damage sets in. Mean intracellular pH when PCr/Pi was minimal was 7.17 +/- 0.10. Values for PCr/Pi below 0.80 were associated with a very bad prognosis for survival and early neuro-developmental outcome.

PRECISION OF ULTRASOUND DIAGNOSIS OF PATHOLOGICALLY VERIFIED LESIONS IN THE BRAINS OF VERY PRETERM INFANTS

Abnormalities detected by a mechanical sector scanner were compared ‘blind’ with autopsy findings in the brains of 56 infants born at less than 33 weeks gestation. Intraventricular haemorrhage was found in 53 of 112 hemispheres and had been accurately diagnosed by ultrasound (sensitivity 91 per cent; specificity 81 per cent). Isolated germinal layer haemorrhage was less successfully identified (sensitivity 61 per cent; specificity 78 per cent); false‐positive diagnoses were partly due to difficulty in distinguishing haemorrhage from the normal choroid plexus in extremely preterm infants. Haemorrhagic parenchymal lesions were correctly identified in nine infants (sensitivity 82 per cent; specificity 97 per cent). Only 11 of 39 hemispheres with histological evidence of hypoxic‐ischaemic injury, without marked bleeding, were correctly identified by ultrasound (sensitivity 28 per cent), mainly because of failure to detect small areas of periventricular leucomalacia and diffuse gliosis. 10 hemispheres with periventricular echodensities thought to represent leucomalacia showed no histological evidence of hypoxic‐ischaemic injury (specificity 86 per cent). Ventricular dilatation in seven infants was always associated with evidence of hypoxic‐ischaemic injury at autopsy.

Probability of neurodevelopmental disorders estimated from ultrasound appearance of brains of very preterm infants.

The neurodevelopmental status of 342 very preterm infants who had undergone prospective ultrasound brainscans was assessed at a median corrected age of 52 weeks. The probabilities for neurodevelopmental disorders were calculated according to the ultrasound findings. The results showed that the probabilité of a major or minor disorder was low for infants whose scans did not show periventricular haemorrhage or markedly increased parenchymal echodensities in the first week of life, and for those whose scans at discharge gave no evidence of ventricular dilatation, hydrocephalus or cerebral atrophy. By contrast, the probabilité of a disorder was very high for infants with markedly increased parenchymal echodensities in the first week, and for infants with evidence of cerebral atrophy at discharge. The majority of the infants could be assigned, on the basis of the ultrasound scan at discharge, either to a large group who were at low risk of neurodevelopmental disorders or to a small group who were at high risk; the remainder were at intermediate risk. These findings may be used as a guide to the prognosis for other infants whose ultrasound scans show similar appearances.

PREDICTION OF NEURODEVELOPMENTAL IMPAIRMENT AT FOUR YEARS FROM BRAIN ULTRASOUND APPEARANCE OF VERY PRETERM INFANTS

The neurodevelopmental status of 171 very preterm infants whose brains had been scanned prospectively with ultrasound was assessed blind at four years using a wide range of tests, including tests of cognitive function. Highly significant correlations were found between the ultrasound appearance of the brain and outcome. The probability of a major neurodevelopmental impairment among the 137 children who had a normal ultrasound scan or uncomplicated periventricular haemorrhage at discharge from the unit was 7 per cent; and for any neurodevelopmental impairment (major plus minor) it was 22 per cent. The probabilities for major, or any, neurodevelopmental impairment among the 18 children who had ventricular dilatation were 33 and 50 per cent, respectively; and for the 16 with hydrocephalus and/or cerebral atrophy (loss of brain‐tissue from any cause) the probabilities were 56 and 69 per cent. Impairments predicted from lesions detected by ultrasound were largely neurological. There was no evidence that cognitive impairments could be predicted among infants free of neurological impairments.

Phosphorus Metabolites and Intracellular pH in the Brains of Normal and Small for Gestational Age Infants Investigated by Magnetic Resonance Spectroscopy

ABSTRACT: The brains of 30 normal preterm and term infants whose birth wt were appropriate for gestational age and 13 who were small for gestational age but healthy were studied by phosphorus magnetic resonance spectroscopy to determine values for metabolite concentration ratios and intracellular pH. In the AGA infants, phosphocreatine/ inorganic orthophosphate increased between 28 and 42 wk of gestational plus postnatal age, suggesting a rise in the phosphorylation potential of brain tissue. At the same time, the concentration of phosphomonoester (mainly phosphoethanolamine) fell and that of phosphodiester (including phosphatidylethanolamine and phosphatidylcholine) increased. These changes reflected myelination and proliferation of membranes. Intracellular pH was ˜7.1 and did not change with brain maturation. No differences were detected in these variables between the infants who were small for gestational age and those who were appropriate for gestational age.

INCREASED PERIVENTRICULAR ECHCDENSITIES IN VERY PRETERM INFANTS AND PREDICTION OF EARLY NEURCDEVELOPMENTAL OUTCOME

Increased periventricular echodensities in preterm infants appear usually to be transient, but occasionally evolve into cystic periventricular leukomalacia. The purpose of this investigation was to find out whether the detection of increased echodensities improved the prognostic significance of abnormalities detected in the brain of very preterm infants by ultrasound scanning. In 1983, the brains of 122 infants born at less than 33 weeks of gestation who were admitted to the Neonatal Unit of University College Hospital were repeatedly scanned. Classification of the results was as previously described (1), but in addition the absence (n=103) or presence (n=19) and degree (+ or ++) of increased periventricular echodensities was noted. Neurodevelopmental assessments (1) were performed on all the infants at 1 year of age. The table shows the prevalence of neurodevelopmental abnormalities (including both major and minor abnormalities) at follow-up.The results provided no evidence that the presence of increased periventricular echodensities aided the assignment of prognosis.1. Stewart AL et al. Arch Dis Child 1983; 58: 598-604.

40 ULTRASOUND BRAIN-SCANS IN VERY PRETERM INFANTS AND OUTCOME AT 18 MONTHS AND 4 YEARS OF AGE

We have previously reported close associations between the results of ultrasound brain-scans in infants born at less than 33w gestation and their neurodevelopmental status at 18 months of age (Stewart AL et al, Arch Dis Child 1983; 58: 598-604). To find out whether this status had changed at 4 years, neurological examinations and tests of cognitive function were carried out (see table).In general, neurodevelopmental status at 18 months was substantiated at 4 years. Disorders recognised at 4 years in previously unaffected infants included deficits of vision and of cognitive function, behavioural disorders and epilepsy. 4 infants no longer had minor disorders but as a group infants assigned this status at 18 months (usually because of abnormalities of tone and reflexes) scored worse on tests of cognitive function than infants considered to be normal at 18 months.

120 SENSITIVITY OF DETECTION OF BRAIN-LESIONS IN VERY PRETERM INFANTS BY ULTRASOUND

To investigate how well ultrasound scanning (US) of the brain detected autopsy-proven lesions, abnormalities detected by a sector scanner with 6 and 7.5 MHz probes were compared blind with the autopsy findings in 57 infants born at less than 33w gestation who died aged 0-166 (median 2) days. Germinal layer-intraventricular haemorrhage (GLH-IVH) was found at autopsy in 71 of the 114 hemispheres and always detected by US (sensitivity 100%, 71/71). The 43 hemispheres with no GLH-IVH at autopsy were thought to show US evidence of GLH in 16 infants and IVH in 4, most of whom were extremely preterm (specificity 53%, 23/43).Parenchymal lesions were present in 50 (44%) of the 114 hemispheres and were predominantly haemorrhagic in 11 and ischaemic in 39. The haemorrhagic lesions were correctly identified in 9 infants (sensitivity 82%, 9/11) and there were 3 false positive diagnoses (specificity 97%, 100/103). Only 11 of the 39 hemispheres with histological evidence of ischaemia were correctly identified by US, mainly because focal periventricular leucomalacia or diffuse gliosis were not detected (sensitivity 28%, 11/39). 10 hemispheres with peri-ventricular echoes thought to represent leucomalacia showed no histological evidence of ischaemia (specificity 87%, 65/75).US is not a sensitive technique for the early detection of lesser degrees of cerebral ischaemic injury in very preterm newborn infants.

20 PHOSPHORUS METABOLITES AND INTRACELLULAR pH IN THE BRAINS OF NORMAL AND GROWTH RETARDED INFANTS

Studies by magnetic resonance spectroscopy were performed at a median age of 5 days on 18 appropriately grown (AGA) and 9 growth retarded (SGA) newborn infants with birthweights below the 3rd centile, to investigate: 1. Maturational changes in cerebral intracellular high-energy phosphorus (P) metabolite concentrations and pHi during normal gestation, and: 2. Whether any abnormalities were detectable in the SGA infants. The methods used have been described previously (Hope PL et al, Lancet 1984, ii: 366).Linear regressions were calculated for P-metabolite concentration ratios and pH. on gestational plus postnatal age for the AGA infants. Phosphocreatine (PCr)/inorganic orthophosphate (Pi) increased from 0.77±0.24 (95% confidence limits) at 28w to 1.09±0.24 at 42w (p<0.001). No significant changes were found in adenosine triphosphate (ATPl/total P, PCr/ATP, Pi/ATP, phosphomonoester (PME)/ATP, phosphodiester (PDE)/ATP, or pH., though PCr/ATP tended to rise, and Pi/ATP and PME/ATP tended to fall. Values from the SGA infants at 30-38w of gestational plus postnatal age were distributed evenly across the data from the AGA infants.We conclude: 1. PCr/Pi increased with advancing maturation of the brain, and: 2. Values for P-metabolite ratios and pHi in the SGA infants did not differ from those in the AGA infants.