Developmental outcome of very preterm babies using an assessment tool deliverable by health visitors.

AIM: To assess the developmental outcome of very preterm infants using a developmental screening tool deliverable by health visitors. METHODS: The study cohort consisted of preterm infants born at <32 weeks gestation or <1500g. Infants were assessed at 12 and 24 months corrected age using the Schedule of Growing Skills developmental screening test. Scores for skill areas were converted to developmental levels in months and graded as normal or mild, moderate or severe delay. RESULTS: Of 101 infants assessed at 12 months, 12 (12%) had severe developmental delay (developmental level <6months) in one or more skill areas. At 24 months, severe developmental delay (developmental level <12 months) was found in 8 (9.1%) infants. Only 3 infants had severe global delay. However, approximately a third of infants showed mild or moderate delay in hearing and language, social or cognitive skill areas by 24 months. CONCLUSION: Developmental assessment undertaken by health visitors may be used to measure outcome in preterm infants. Severe developmental delay was at a level consistent with other follow-up studies of very preterm infants. Severe delay was identified by the 12-month check and was mainly in areas of motor function and language. High levels of mild to moderate developmental delay were identified at the 24-month assessment.

Diagnostic value of subependymal pseudocysts and choroid plexus cysts on neonatal cerebral ultrasound: a meta-analysis.

BACKGROUND AND OBJECTIVE: Subependymal pseudocysts and choroid plexus cysts are seen in newborns on cerebral ultrasound. Clinicians are unsure whether these findings are related to an underlying disease which affects long-term outcome and requires medical intervention. In an attempt to establish the diagnostic value of cystic lesions on cerebral ultrasound and guide clinical management we searched the medical literature and performed a meta-analysis. METHODS: We performed a systematic literature review and summarised the data on the value of subependymal pseudocysts or choroid plexus cysts for the diagnosis of chromosomal anomalies or congenital infections. Sensitivity, specificity, predictive values and likelihood ratios were calculated for single, multiple, unilateral and bilateral cysts. RESULTS: 305 patients with cystic lesions were retrieved. Bilateral cysts, irrespective of their number, had a sensitivity of 88% and negative predictive value of 94% for a congenital infection or genetic disorder. Unilateral single cysts had a specificity of 92% for normal microbiological and genetic results. Bilateral multiple subependymal pseudocysts or choroid plexus cysts had a positive likelihood ratio of 9.1 for a chromosomal anomaly or congenital infection. Unilateral cysts had a negative likelihood ratio of 0.2 for a congenital infection or chromosomal anomaly. There was a chance of 1 in 4-5 for a congenital infection or chromosomal anomaly if bilateral multiple subependymal pseudocysts or choroid plexus cysts were found. CONCLUSIONS: Bilateral multiple subependymal pseudocysts or choroid plexus cysts suggest an underlying disease. Further investigations should be undertaken even if the patient is otherwise normal. Parents of well newborns with a single cyst should be reassured.

Early prediction of neurological outcome by term neurological examination and cranial ultrasound in very preterm infants.

AIM: To assess the value of term neurological examination and cranial ultrasound in the early prediction of neurological outcome at 12 months corrected age in a cohort of very preterm infants. METHODS: A cohort of 102 preterm infants born at <32 weeks gestation or with a birth weight of <1500 g were assessed using the Hammersmith Term Neurological Examination. They underwent cranial ultrasound examinations according to local guidelines. The Hammersmith Infant Neurological Examination was performed at 12 months corrected age. Scores for the term examinations were compared with scores derived from healthy infants born at term and with scores from low-risk preterm infants at term equivalent age. Term neurological scores and cranial ultrasound findings were compared in the prediction of 12-month neurological outcome. RESULTS: Seventy-eight (76.5%) preterm infants had suboptimal total neurological scores at term when compared to healthy infants born at term. However, most went on to have optimal neurological scores at 12 months corrected age. When our cohort was compared with low-risk preterm infants at term equivalent age only 14 (13.7%) scored outside the normal range. Neither system of scoring predicted neurological outcome at 12 months corrected age as reliably as cranial ultrasound (sensitivity 0.83, specificity 0.87). CONCLUSION: Neurological examination of preterm babies at term may be unreliable in the prediction of neurological outcome at 12 months corrected age. For early prediction of neurological outcome cranial ultrasound examination was found to be more reliable.

Use of red cells preserved in extended storage media for exchange transfusion in anti-k haemolytic disease of the newborn.

Anti-k is a Kell-related antibody. There is little correlation between the maternal antibody titre and the severity of haemolytic disease of the foetus and newborn, and anaemia is usually associated with low bilirubin levels. Severe erythroblastosis has been reported with a low titre anti-k (IAT 8-16). We report a case of severe haemolytic disease of the newborn (HDN) due to anti-k. HDN was associated with a normal bilirubin level and reticulocytopenia. The foetus was monitored by ultrasound, and delivery by elective caesarean section (CS) was planned. The mother was admitted 1 week before the expected date of delivery, and the infant was delivered by urgent CS. The infant required exchange transfusion. As suitable plasma-reduced (k antigen(-)) red cell units were not readily available, k- SAGM red cell units (preserved in extended storage media: SAGM sodium chloride, adenine, glucose and mannitol) were provided. The post-transfusion Hb remained stable, and the infant did not require further transfusion support. Our findings (reticulocytopenia and normal bilirubin levels) support the hypothesis that the pathogenesis of anaemia and haemolysis in anti-k HDN may be similar to that in anti-K (suppression of erythropoesis and immune destruction of K+ erythroid progenitor cells by macrophages in the foetal liver). The ideal product for exchange transfusion is plasma-reduced RBC, less than 5-days old. We provided a 4-day-old SAGM red cell unit for exchange transfusion in a term infant, and this was uneventful. Caution should be taken, however, and renal function and electrolyte levels should be monitored closely. More information is required regarding the safety of SAGM units for exchange transfusion.

A comparision of linear-array and mechanical-sector cranial ultrasound scanning techniques to predict neurodevelopmental outcome at 8 years in preterm newborn infants.

Two methods of neonatal cranial ultrasound (US) scanning, linear-array and mechanical-sector, were compared for their accuracy in predicting neurodevelopmental outcome in a cohort of 854, of whom 782 (92%) infants, all born less than 33 weeks of gestation and cared for on the Neonatal Intensive Care Unit at University College Hospital, London between 1979 and 1988, were included in the analysis. A total of 205 infants were studied by linear-array and 577 infants by mechanical-sector scan. Ultrasound findings were grouped into three risk categories on the basis of the US diagnosis. Outcome was assessed at 8 years of age. The probability estimates for neurologically disabling and nondisabling impairments, extra education and mean IQ were compared for the two US methods. There was no significant difference between the two methods in the accuracy of prediction of neurodevelopmental outcome.

Magnesium sulfate treatment after transient hypoxia-ischemia in the newborn piglet does not protect against cerebral damage.

Transient perinatal hypoxia-ischemia (HI) can lead to delayed cerebral damage beginning 8-24 h after resuscitation. Cerebroprotective therapies applied soon after HI may thus reduce the severity of brain injury. We have previously shown that MgSO4 administration to newborn piglets after HI fails to prevent the delayed global impairment in cerebral energy metabolism characteristic of severe brain damage. However, high extracellular concentrations of magnesium ions have been found to prevent specific excitotoxic neural cell death in vivo and in vitro. This study therefore examined the hypothesis that MgSO4 administration after HI reduces damage in some regions of the brain even though global energy metabolism is unaffected. Twelve newborn piglets were subjected to global cerebral HI by transient occlusion of both common carotid arteries and reduction of the inspired oxygen fraction to 0.12 until cerebral high-energy phosphates, measured by magnetic resonance spectroscopy, were significantly depleted. Subjects were randomly assigned to two groups of six: the first received MgSO4 (three doses, 400 mg/kg 1 h after resuscitation and 200 mg/kg at 12 and 24 h), and the second received placebo infusions. At 48 h after the start of the experiment, the piglets were killed and their brains were perfused, fixed, and embedded in paraffin wax. Five-micrometer sections were stained with hematoxylin and eosin to allow semiquantitative analysis of the severity and extent of injury to the hippocampus, cerebellum, cerebral cortex, caudate nucleus, thalamus, and striatum and the white matter tracts. There was no difference in the severity of tissue damage between the MgSO4-treated group and the placebo-treated animals in any brain region.

Cerebral tissue water spin-spin relaxation times in human neonates at 2.4 tesla: methodology and the effects of maturation.

Using a 4-echo spin-echo sequence, cerebral T2 was measured in specific anatomic regions in eleven healthy newborn infants, whose gestational plus postnatal ages (GPAs) lay between 37 and 42 weeks. For a region in the pons, T2 was 141+/-9 ms (mean +/- standard deviation), and no significant dependence upon GPA was seen. In the thalamus mean T2 was 136+/-13 ms, and T2 demonstrated a significant negative linear dependence upon age (r = 0.690; p < 0.02). In periventricular and frontal regions, mean T2 were 217+/-33, and 228+/-32 ms respectively, and more marked negative linear correlations with age were observed (r = 0.833; p < 0.001 and r = 0.722; p < 0.02). For these regions, the rate of T2 decrease with age appeared to be related to known patterns of myelination. For the parietal region studied, mean T2 was 204+/-34 ms, no significant dependence upon GPA being seen. T2 shows promise as an objective measure of cerebral development in the perinatal period.

Early brain proton magnetic resonance spectroscopy and neonatal neurology related to neurodevelopmental outcome at 1 year in term infants after presumed hypoxic-ischaemic brain injury.

This study investigated the accuracy of prediction of neurodevelopmental outcome at 1 year using cerebral proton magnetic resonance spectroscopy (MRS) and structured neonatal neurological assessment in term infants after presumed hypoxic-ischaemic brain injury. Eighteen control infants and 28 infants with presumed hypoxic-ischaemic brain injury underwent proton MRS investigation. Studies were carried out as soon as possible after the cerebral insult, most within 48 hours. Infants had an early structured neurological assessment at a median of 19 hours (range 0 hours to 9 days) from the presumed hypoxic-ischaemic insult and a late assessment at a median of 7 days (range 3 to 25 days) during recovery. The maximum cerebral peak-area ratio lactate:N-acetylaspartate measured by proton MRS accurately predicted adverse outcome at 1 year with a specificity of 93% and positive predictive value of 92%. Neurological assessment had a tendency for false-positive predictions. However, both early and late neurological examination can be used as a reliable indicator for a favourable outcome at 1 year having negative predictive values of 100% and 91% respectively.

Brain structure and neurocognitive and behavioural function in adolescents who were born very preterm.

BACKGROUND: Infants born very preterm (<33 weeks) are at increased risk of neurocognitive deficits. Their neurodevelopmental outcome up to age 8 years can be predicted by neonatal ultrasonography, but little is known of their later function. We investigated the effect of very preterm birth on brain structure and neurocognitive and behavioural functioning in adolescence. METHODS: A cohort of 105 infants born before 33 weeks of gestation in 1979-80 had ultrasonographic scans at University College Hospital, London, and were prospectively examined at 1, 4, and 8 years. At age 14-15 years, 72 of those who remained in UK (cases) and 21 age-matched full-term controls underwent brain magnetic resonance imaging (MRI), as well as neurological, cognitive, and behavioural assessment. MRI images were assessed by two neuroradiologists unaware of ultrasonographic findings or case or control status. FINDINGS: Of the 72 cases, 40 had unequivocally abnormal MRI and 15 had equivocal scans. Of the 21 controls, one had abnormal and five equivocal MRI. Abnormalities of ventricles, corpus callosum, and white matter were especially common in cases. More brain lesions were identified by MRI than by neonatal ultrasonography. The cases had significantly more reading, adjustment, and neurological impairments than controls, but their behaviour was significantly related to MRI abnormality. INTERPRETATION: Individuals born very preterm show an excess of neurocognitive and behavioural problems in adolescence, and more than half have abnormal MRI brain scans.

Use of mitochondrial inhibitors to demonstrate that cytochrome oxidase near-infrared spectroscopy can measure mitochondrial dysfunction noninvasively in the brain.

The use of near-infrared spectroscopy to measure noninvasively changes in the redox state of cerebral cytochrome oxidase in vivo is controversial. We therefore tested these measurements using a multiwavelength detector in the neonatal pig brain. Exchange transfusion with perfluorocarbons revealed that the spectrum of cytochrome oxidase in the near-infrared was identical in the neonatal pig, the adult rat, and in the purified enzyme. Under normoxic conditions, the neonatal pig brain contained 15 micromol/L deoxyhemoglobin, 29 micromol/L oxyhemoglobin, and 1.2 micromol/L oxidized cytochrome oxidase. The mitochondrial inhibitor cyanide was used to determine whether redox changes in cytochrome oxidase could be detected in the presence of the larger cerebral hemoglobin concentration. Addition of cyanide induced full reduction of cytochrome oxidase in both blooded and bloodless animals. In the blooded animals, subsequent anoxia caused large changes in hemoglobin oxygenation and concentration but did not affect the cytochrome oxidase near-infrared signal. Simultaneous blood oxygenation level-dependent magnetic resonance imaging measurements showed a good correlation with near-infrared measurements of deoxyhemoglobin concentration. Possible interference in the near-infrared measurements from light scattering changes was discounted by simultaneous measurements of the optical pathlength using the cerebral water absorbance as a standard chromophore. We conclude that, under these conditions, near-infrared spectroscopy can accurately measure changes in the cerebral cytochrome oxidase redox state.

MRI measurements of cerebral deoxyhaemoglobin concentration [dHb]--correlation with near infrared spectroscopy (NIRS).

Changes in physiological parameters such as cerebral blood flow, cerebral blood volume, oxygen extraction, and the size and distribution of cerebral blood vessels, result in changes in the local concentration of deoxyhaemoglobin ([dHb]). The purpose of this study was to quantitatively investigate the dependence of the R2* relaxation rate upon the [dHb] per voxel. Five neonatal piglets were studied in a 7 T/20 cm bore magnet. MRI was conducted using a 2.5 cm diameter surface coil placed over the parietal lobes. Four progressively T2*-weighted images were acquired, allowing the absolute quantitation of R2*. Simultaneous near infrared spectroscopy (NIRS) measurements were made from an area encompassing the MR imaging slice, and allowed the absolute quantitation of [dHb]. The arterial oxygen saturation (SaO2) of the piglet was lowered stepwise by decreasing the fractional inspired oxygen concentration (FiO2), which precipitated a change in [dHb]. NIRS and MRI measurements were made at each FiO2 step. The results demonstrate an extremely strong, linear relationship between R2* as determined by MRI and [dHb], as measured by NIRS. Whereas NIRS can only give us a global measure of [dHb], the results suggest the future use of MRI in producing high resolution relaxation rate maps related to the [dHb] distribution of the brain.

Temporal and anatomical variations of brain water apparent diffusion coefficient in perinatal cerebral hypoxic-ischemic injury: relationships to cerebral energy metabolism.

Cerebral apparent diffusion coefficients (ADCs) were determined in nine newborn piglets before and for 48 h after transient hypoxia-ischemia. Phosphorus MRS revealed severely reduced cerebral energy metabolism during the insult and an apparently complete recovery 2 h after resuscitation commenced. At this time, mean ADC over the imaging slice (ADCglobal) was 0.88 (0.04) x 10(-9) m2 x s(-1) (mean (SD)), which was close to the baseline value of 0.92 (0.4) x 10(-9) m2 x s(-1). In seven of the animals, a "secondary" failure of energy metabolism then evolved, accompanied by a decline in ADCglobal to 0.64 (0.17) x 10(-9) m2 x s(-1) at 46 h postresuscitation (P < 0.001 versus baseline). For these seven animals, ADCglobal correlated linearly with the concentration ratio [phosphocreatine (PCr)]/[inorganic phosphate (Pi)] (0.94 < r < 0.99; P < 0.001). A nonlinear relationship was demonstrated between ADCglobal and the concentration ratio [nucleotide triphosphate (NTP)]/[Pi + PCr + 3 NTP]. The ADC reduction commenced in the parasagittal cortex before spreading in a characteristic pattern throughout the brain. ADC seems to be closely related to cerebral energy status and shows considerable potential for the assessment of hypoxic-ischemic injury in the newborn brain.

Acquired spinal cord lesion associated with os odontoideum causing deterioration in dystonic cerebral palsy: case report and review of the literature.

A boy with a dystonic quadriparesis presented with acquired paralysis, spasticity, and a feeding disorder. Spinal MRI revealed a cervical cord lesion and os odontoideum. Excessive movement of the neck, leading to failure of ossification of the dens and then to cervical cord trauma was the likely mechanism. The poor outcome of this subject is described, emphasising the need to pay careful attention to neurological changes in children with extrapyramidal cerebral palsy, who may be at particular risk of cord pathology. The management issues are discussed.

Organ pathology following mild hypothermia used as neural rescue therapy in newborn piglets.

The aim of this study was to assess the possible adverse effects of hypothermia, used as neural rescue therapy in a newborn piglet model. Sixteen newborn piglets were subjected to transient cerebral hypoxia-ischaemia by temporary occlusion of the carotid arteries and reduction of the fractional inspired oxygen to 0.12. On resuscitation 11 piglets were maintained normothermic (38.5-39.0 degrees C) and, in order to assess the cerebroprotective effect of hypothermia, 5 piglets were cooled to 35 degrees C for 12 h before normothermia was resumed. At 48 or 64 h following resuscitation the animals were sacrificed and the heart, left kidney, specimens of distal small bowel, lung and liver were removed and histologically sectioned. No microscopic abnormalities of the heart, bowel or lung were observed in hypothermic or normothermic animals. All kidney specimens were normal except one from the normothermic group. Abnormal liver pathology suggestive of hypoperfusion injury was found in 5 normothermic and 3 hypothermic piglets. There was no significant difference in the proportion of piglets with liver abnormality between the two groups. Mild hypothermia following cerebral hypoxia-ischaemia in the newborn piglet was not associated with an increased incidence of non-cerebral organ damage. The hepatic injury observed may be related to umbilical venous catheterisation and has potential relevance to neonatal intensive care.

Epilepsy in very preterm infants: neonatal cranial ultrasound reveals a high-risk subcategory.

The aim of this study was to investigate the association between epilepsy and perinatal brain injury in a cohort of 610 infants born preterm at <33 weeks' gestation. The prevalence of epilepsy in this cohort was 4.3% as determined by a postal questionnaire survey. Most children with epilepsy (16 of 24) had high-risk cranial ultrasound lesions including haemorrhagic parenchymal infarction (HPI), posthaemorrhagic hydrocephalus, and cystic periventricular leukomalacia (PVL). Of all the children in our cohort with high-risk brain lesions, those with epilepsy were more likely to have HPI and significantly less likely to have cystic PVL, although it is possible that PVL was not noticed in some cases. Children with epilepsy and high-risk cranial ultrasound lesions also showed more cognitive impairment than children with high-risk lesions but no epilepsy, which suggested more cortical grey-matter damage. We suggest that brain injury has occurred outside the confines of the periventricular white matter in this group of preterm infants with epilepsy.

Proton magnetic resonance spectroscopy of the brain during acute hypoxia-ischemia and delayed cerebral energy failure in the newborn piglet.

Studies of the brains of severely birth-asphyxiated infants using proton (1H) magnetic resonance spectroscopy (MRS) have shown changes indicating a rise in cerebral lactate (Lac) and a fall in N-acetylaspartate (Naa). The aim of this study was to test two hypotheses: 1) that these changes can be reproduced in the newborn piglet after transient reversed cerebral hypoxiaischemia, and their time course determined; and 2) that changes in Lac peak-area ratios are related to changes in phosphorylation potential as determined by phosphorus (31P) MRS. Eighteen piglets aged < 24 h were anesthetized and ventilated. Twelve underwent temporary occlusion of the carotid arteries and hypoxemia, and six served as sham-operated controls. 1H and 31P spectra were acquired alternately, both during the insult and for the next 48 h, using a 7-tesla spectrometer. During hypoxiaischemia, the median Lac/total creatine (Cr) peak-area ratio rose from a baseline of 0.14 (interquartile range 0.07-0.27), to a maximum of 4.34 (3.33-7.45). After resuscitation, Lac/Cr fell to 0.75 (0.45-1.64) by 2 h, and then increased again to 2.43 (1.13-3.08) by 48 h. At all stages after resuscitation Lac/Cr remained significantly above baseline and control values. Naa/Cr was significantly reduced below baseline and control values by 48 h after resuscitation. The increases in the Lac peak-area ratios were concomitant with the falls in the [phosphocreatine (PCr)*]/ [inorganic phosphate (Pi)] ratio, during both acute hypoxiaischemia and delayed energy failure. The maximum Lac/Naa during delayed energy failure correlated strongly with the minimum [nucleotide triphosphate (NTP)]/[exchangeable phosphate pool (EPP)] (r = -0.94, p < 0.0001). We conclude that both hypotheses have been confirmed.

Mild hypothermia after severe transient hypoxia-ischemia reduces the delayed rise in cerebral lactate in the newborn piglet.

This study tested the hypothesis that mild hypothermia after severe transient hypoxia-ischemia reduces the subsequent delayed rise in cerebral lactate peak-area ratios as determined by proton (1H) magnetic resonance spectroscopy (MRS) in the newborn piglet. Nine piglets aged < 24 h underwent temporary occlusion of the common carotid arteries and hypoxemia. Resuscitation was started when cerebral [phosphocreatine]/[inorganic phosphate] had fallen close to zero and [nucleotide triphosphate (NTP)]/[exchangeable phosphate pool (EPP)] was below about a third of baseline. On resuscitation rectal and tympanic temperatures were lowered to 35 degrees C for 12 h after which normothermia (38.5 degrees C) was resumed. 1H MRS data collected over 48 or 64 h after resuscitation were compared with concurrently established data from 12 piglets similarly subjected to transient cerebral hypoxia-ischemia, but maintained normothermic, and six sham-operated controls. The severity of the primary insult (judged from the time integral of depletion of [NTP]/[EPP]) was similar in the hypothermic and normothermic groups. The maximum lactate/N-acetylaspartate ratio observed between 24 and 48 h after resuscitation in the hypothermic group was 0.10 (0.05-0.97), median (interquartile range), which was significantly lower than that observed in the normothermic group, 1.28 (0.97-2.14), and not significantly different from that observed in the control group, 0.08 (0.06-0.11). Similar results were obtained for lactate/choline and lactate/total creatine. We conclude that mild hypothermia after a severe acute cerebral hypoxic-ischemic insult reduces the delayed elevation in lactate peak-area ratios, thus reflecting reduced lactate accumulation.