Ultrasound and necropsy study of periventricular haemorrhage in preterm infants.

The diagnostic accuracy of cerebral ultrasound for periventricular haemorrhage was determined by comparing this with necropsy findings in 30 preterm neonates of 30 weeks'' gestation or less and birthweight under 1500 g. Ultrasound gave an accurate diagnosis of 85% in infants with germinal layer haemorrhage, 92% in intraventricular haemorrhage, and 97% in intracerebral haemorrhage. False positive errors were caused by vascular congestion; false negative errors occurred when the maximum dimension of haemorrhage was less than 3 mm. Cerebral ultrasound gave a diagnostic accuracy of 63% for periventricular leucomalacia. False negative errors occurred when periventricular leucomalacia was microscopic or when it was out of range of the scanner. The maximum width of the germinal layer was measured in 77 neonates of gestational age 23 to 36 weeks who died and had no periventricular haemorrhage at necropsy. The progressive involution of the germinal layer with increasing gestational age paralleled the steady decrease in incidence of periventricular haemorrhage diagnosed over the same gestational age range. Neonates of the youngest gestational age who had the most extensive germinal layers also had the highest risk for periventricular haemorrhage.     

Periventricular leucomalacia and intraventricular haemorrhage in the preterm neonate.

Two hundred very low birthweight infants were prospectively scanned to ascertain the incidence of periventricular leucomalacia (PVL) and haemorrhage. Before collection of data, clear definitions of ultrasound abnormalities believed to represent PVL and intraventricular haemorrhage were described. These referred to small and moderate intraventricular haemorrhage, paenchymal haemorrhage, and PVL, including prolonged flare (echoes in the periventricular region lasting for two weeks or more and not becoming cystic). Sixty nine infants (34%) had no abnormality on ultrasound scans. Intraventricular haemorrhage occurred in 107 babies (37 grade I and 62 grade II), and only eight infants were thought to have true parenchymal haemorrhage. Ultrasound appearances of PVL were seen in 27 infants, 19 of whom developed cysts and eight died in the precystic stage. Prolonged flare occurred in another 25 babies. Unilateral parenchymal haemorrhage occurred in four infants who subsequently developed cystic PVL in the contralateral hemisphere. Twenty one infants developed ventricular dilatation, 12 of whom had associated parenchymal lesions. Haemorrhage, PVL, and flare occurred commonly in infants of 30 weeks'' gestation and below and became markedly less common in more mature infants. We believe prolonged flare represents a form of PVL, and in this study a total of 52 (26%) infants had an ultrasound appearance of periventricular leucomalacia, an incidence considerably higher than previously reported.     

A study of periventricular haemorrhage, post-haemorrhagic ventricular dilatation and periventricular leucomalacia in Chinese preterm infants

Serial cranial ultrasound scans were performed in 178 preterm Chinese infants (gestation less than 35 weeks, birthweight less than 2000 g) to study the incidence, age of onset and associating risk factors of periventricular haemorrhage (PVH), and also the occurrence of post-haemorrhagic ventricular dilatation and periventricular leucomalacia (PVL). Sixty-four infants developed haemorrhage, giving an incidence of 36%. Among infants of birthweight less than 1500 and less than 1000 g the respective incidence was 52 and 69%. Seventy-two per cent (46 of 64) of haemorrhages were initially detected within the first 3 days of life, but delayed haemorrhage occurring after 1 week of age occurred in nine infants. In eight of these infants PVH had been shortly preceded by a major clinical disaster. Eleven perinatal factors were found to be significantly associated with PVH but only systemic hypotension showed a significant independent association. Post-haemorrhagic ventricular dilatation developed in 17 (46%) of the 37 infants who survived for more than 1 month after PVH. This was transient in 41%, persistent but stable in 29% and progressive in 29%. PVL was detected in eight infants who survived the initial period following PVH.     

Clinical risk factors and periventricular leucomalacia.

Two hundred infants of below 1501 g at birth were regularly examined with real time ultrasound using a 7.5 MHz transducer. Abnormalities were categorized as periventricular haemorrhage (PVH) (n = 107) or periventricular leucomalacia (PVL), with or without PVH (n = 52). Of the group with PVL, 25 had the appearances of prolonged flare without cavitation. Prospective assessments of up to 50 potential clinical risk factors were made wherever possible on each infant including stratification of all blood gas and systolic blood pressure data. Multivariate logistic regression analyses confirmed a strong correlation between immaturity and PVH but this was not found in cases of PVL. Independent variables associated with PVL included pneumothorax, maximum bilirubin concentration, surgery, and the proportion of time the infant''s PaCO2 remained above 7 kPa. There was a very strong inverse correlation between anaemia and PVL. Systolic blood pressure data were carefully analysed and there was no relation between either hypotension or antepartum haemorrhage and the development of PVL.     

Neurodevelopmental outcome of periventricular haemorrhage and leukomalacia in infants 1250 g or less at birth

The brains of 50 consecutively admitted infants weighing 1250 g or less at birth were serially examined beyond the neonatal period for periventricular haemorrhage and for periventricular leukomalacia with real-time ultrasound. There was significant correlation between the presence or absence and the severity of haemorrhage with survival. A prospective neurodevelopmental assessment was completed at 2 years of age, corrected for prematurity, on all survivors. None of the 20 survivors with normal scans or germinal layer haemorrhages had evidence of major disability and all four survivors with intracerebral haemorrhage or periventricular leukomalacia had major disability. The mental performance on the Bayley scales of infant development was also significantly worse in the latter group. Six of the eight survivors with intraventricular haemorrhage had no major disability, including three who had post-haemorrhagic hydrocephalus. Our results showed that cerebral ultrasound detection of brain pathology is a good predictor of neurodevelopmental outcome in such extremely low birthweight infants. However, as the maximum extent of periventricular haemorrhage may develop beyond one week of age and cystic periventricular leukomalacia commonly develops after the neonatal period, serial scanning is mandatory to ensure diagnostic accuracy for both periventricular haemorrhage and leukomalacia.     

Early postnatal dexamethasone treatment and increased incidence of cerebral palsy

OBJECTIVE: To study the long term neurodevelopmental outcome of children who participated in a randomised, double blind, placebo controlled study of early postnatal dexamethasone treatment for prevention of chronic lung disease. METHODS: The original study compared a three day course of dexamethasone (n = 132) with a saline placebo (n = 116) administered from before 12 hours of age in preterm infants, who were ventilated for respiratory distress syndrome and had received surfactant treatment. Dexamethasone treatment was associated with an increased incidence of hypertension, hyperglycaemia, and gastrointestinal haemorrhage and no reduction in either the incidence or severity of chronic lung disease or mortality. A total of 195 infants survived to discharge and five died later. Follow up data were obtained on 159 of 190 survivors at a mean (SD) age of 53 (18) months. RESULTS: No differences were found between the groups in terms of perinatal or neonatal course, antenatal steroid administration, severity of initial disease, or major neonatal morbidity. Dexamethasone treated children had a significantly higher incidence of cerebral palsy than those receiving placebo (39/80 (49%) v. 12/79 (15%) respectively; odds ratio (OR) 4.62, 95% confidence interval (95% CI) 2.38 to 8.98). The most common form of cerebral palsy was spastic diplegia (incidence 22/80 (28%) v. 5/79 (6%) in dexamethasone and placebo treated infants respectively; OR 4.45, 95% CI 1.95 to 10.15). Developmental delay was significantly more common in the dexamethasone treated group (44/80 (55%)) than in the placebo treated group (23/79 (29%); OR 2. 87, 95% CI 1.53 to 5.38). Dexamethasone treated infants had more periventricular leucomalacia and less intraventricular haemorrhage in the neonatal period than those in the placebo group, although these differences were not statistically significant. Eleven children with cerebral palsy had normal ultrasound scans in the neonatal period; all 11 had received dexamethasone. Logistic regression analysis showed both periventricular leucomalacia and drug assignment to dexamethasone to be highly significant predictors of abnormal neurological outcome. CONCLUSIONS: A three day course of dexamethasone administered shortly after birth in preterm infants with respiratory distress syndrome is associated with a significantly increased incidence of cerebral palsy and developmental delay.     

Brain maturation and damage in infants dying from chronic pulmonary insufficiency in the postneonatal period

The changes in the brains of 11 infants who survived from 29 days to 13 months after severe chronic pulmonary insufficiency are described.Brain maturation as assessed by myelination and gyral formation was within normal limits. In 5 infants the brain weight was less than normal if age was used in the comparison, but greater than normal if body weight was used.In addition to hypoxic or ischaemic damage, which was found in some degree in all cases except one, there were several other local lesions. These included periventricular leucomalacia 7, periventricular haemorrhage 1, hydrocephalus 2, and cystic encephalomalacia 3. Though the last is almost certainly due to vascular occlusion, this could not be shown. The possibility of cerebral embolism after umbilical vein catheterization is considered but not proven.     

Patent ductus arteriosus and cystic periventricular leucomalacia in preterm infants

AIM: To test the association between early disturbances in hemodynamics induced by left-to-right shunting through the duct and cystic periventricular leucomalacia. PATIENTS: Forty-six preterm infants (27-32 wk) admitted to the neonatal intensive care unit with risk criteria. METHODS: Patent ductus arteriosus was evaluated on days 1 and 4, and was significant (sPDA) in cases of absent or reversed end diastolic flow in the subductal aorta. Resistance index was measured in the anterior cerebral artery and in the subductal aorta. MAIN OUTCOME: Diagnosis of cystic periventricular leucomalacia between day 10 and day 50. RESULTS: The 12 infants who developed cystic periventricular leucomalacia were compared with those who did not. On day 1, sPDA was more frequent (64% vs 26%; p = 0.03) in the cystic periventricular leucomalacia group, left ventricular output was higher (median = 341 vs 279 ml kg-1.min-1; p = 0.005), and rescue surfactant was more frequently used (83% vs 47%; p = 0.03). This latter association was confirmed by multivariate analysis. Resistance index in the anterior cerebral artery was increased in cases of significant patent ductus arteriosus (p < 0.01) and was correlated with resistance index in the subductal aorta. CONCLUSION: On day 1 in this selected population, sPDA has an effect on blood flow velocity waveform in cerebral arteries and is associated with an increase in the emergence of cystic periventricular leucomalacia. This association could be casual rather than causal.     

Ultrasound appearance of the brain in very preterm infants and neurodevelopmental outcome at 18 months of age.

The brains of 158 consecutively admitted very preterm infants were repeatedly examined with real time ultrasound. Abnormalities, most commonly periventricular haemorrhage, were detected in 79 (50%). The 109 infants who survived were followed up until they were 16-23 months old. Major or minor neurological or developmental sequelae were found in 5 of 62 infants (8%) with normal ultrasound scans and in an identical proportion, 2 of 25 infants (8%), with uncomplicated periventricular haemorrhage. By contrast, 15 of 21 infants (71%) whose ventricles became enlarged (with or without periventricular haemorrhage) had abnormalities at follow up. The proportion with sequelae depended on the cause and extent of the enlargement. Three of 8 infants (38%) with mild (usually transient) ventricular distension had sequelae, compared with 3 of 4 (75%) with hydrocephalus and 9 of 9 (100%) with cerebral atrophy (2 of whom also had hydrocephalus). Adverse neurodevelopmental sequelae at follow up appeared more often to be attributable to cerebral ischaemia and infarction than to periventricular haemorrhage.     

Structure and evolution of echo dense lesions in the neonatal brain. A combined ultrasound and necropsy study.

Sixty seven of 216 infants weighing less than 2 kg at birth had cerebral lesions on ultrasonic scanning. Eight of 17 who had periventricular leukomalacia, with or without subependymal or intraventricular haemorrhage, or both, died. These and one larger baby were the subject of a combined ultrasound, and where appropriate, necropsy study. There was excellent correlation between the ultrasound and necropsy findings, only some of the earlier lesions of periventricular leukomalacia being missed by ultrasound. The data suggest it is now possible to distinguish periventricular leukomalacia and subependymal/intraventricular haemorrhage by ultrasound, that both lesions may be present in the same brain, that apparent parenchymal extension of an intraventricular haemorrhage is more probably the result of haemorrhage into ischaemic periventricular tissue, and that the term ''periventricular haemorrhage'' should be abandoned since it confuses two lesions of differing aetiology and differing clinical importance. Future advances in neonatal brain ultrasound depend on accurate assessment of both the nature and site of lesions within the cerebral hemispheres and ventricular system since the interpretation of these parameters is of critical importance.     

Neonatal intracranial lesions following placenta abruption

A case-controlled study of the cerebral ultrasound appearances of neonates following placental abruption was undertaken. Twenty-nine index subjects (median gestation 29 weeks) were identified over a 2-year period with gestation-and sex-matched controls. Placental abruption was associated with a fourfold increased incidence of periventricular leukomalacia and extensive periventricular haemorrhage, without increased mortality. Ten infants (34%) developed cystic periventricular leukomalacia following placental abruption, compared with three (10%) in the control group. Intraventricular haemorrhage (excluding subependymal haemorrhage) and haemorrhage into the brain parenchyma occurred in 21 (72%) infants in the abruption group, compared with 14 (48%) in the control group (P<0.05).     

Periventricular leucomalacia and neurodevelopmental outcome in preterm infants.

During an 18 month period, 120 preterm infants of 34 weeks'' gestation or less were prospectively examined for periventricular leucomalacia (PVL) by cerebral ultrasound. Neurological and developmental assessment was carried out at 18 months of age corrected for prematurity in 82 surviving neonates. The developmental outcome (Griffiths development quotient) was above 80 and similar in infants with normal scans (n = 41), isolated periventricular-intraventricular haemorrhage (n = 13), and post-haemorrhagic hydrocephalus (n = 4), and no major handicap was diagnosed in these groups. By contrast, the prognosis was variable and poorer in infants with PVL (n = 24) and depended on the extent and site of the lesion. Infants with frontal PVL (n = 13) developed normally. Major sequelae (n = 8) were closely related to frontal-parietal PVL and frontal-parietal-occipital PVL and could be ascribed to the presence of cysts as well as to a persistent hyperechogenic ultrasonographic PVL appearance. A relation between size and site of the lesion and type and severity of the handicap was established.     

Positive rolandic sharp waves in the EEG of the premature newborn: a five year prospective study.

In a prospective study of 301 premature newborn infants, neonatal tracings were done to evaluate the use of the electroencephalogram (EEG) and positive rolandic sharp waves (PRSW) in the diagnosis and prognosis of periventricular leucomalacia. Each infant had ultrasonographic studies and standardised neurological examinations at 1 year of age or later. Two hundred and eighty infants were followed up at 1 year. This study demonstrated that the absence of PRSW was correlated with a favourable motor development (98.2%) and confirmed the great value of PRSW in the diagnosis and the prognosis of periventricular leucomalacia. PRSW were sensitive (98%) and specific (84%) markers of developmental motor disability and were a sensitive (96%) marker of severe spastic diplegia. A frequency above 2/minute was a specific (92%) sign of severe spastic diplegia. Social and language developmental abnormalities were not correlated with the neonatal EEG.     

Timing and evolution of periventricular haemorrhage in infants weighing 1250 g or less at birth.

The brains of 50 consecutively admitted infants who weighed 1250 g or less at birth were examined with real time ultrasound. Of 30 (60%) who had periventricular haemorrhage (PVH), 19 (63%) bled on the first day and 17 (57%) showed extension of the initial haemorrhage on serial scans. The median age was 16 hours when PVH was first detected and 48 hours when PVH reached its maximum extent. Ventricular size at birth correlated with gestation. Progressive ventricular growth was seen after birth in infants both with and without PVH. Charts of normal ranges of ventricular size and head circumference were drawn up from birth to 10 weeks of age. All infants with PVH showed a transient increase in ventricular size at 2 weeks of age but most returned to normal by 6 weeks of age. Ventricular dilatation after PVH that was greater than the 95th centile for this population developed in 5 (31%) of 16 survivors, four of whom subsequently developed hydrocephalus, although none required ventriculo peritoneal shunting. The optimal timing for diagnosis with ultrasound is at the end of the first week for PVH and the second to third week for ventricular dilatation.     

Risk factors and determinants of neurodevelopmental outcome in cystic periventricular leucomalacia

The aim of the study was to determine risk factors for the development of cystic periventricular leucomalacia (PVL) and to correlate ultrasound findings with neurodevelopmental outcome. By means of a retrospective case-control study (matched for gestational age, birth weight, sex, and year of birth) and a cohort analysis of all preterm infants with cystic PVL documented by ultrasound scans hospitalised at a local tertiary care centre between 1988 and 1998, 98 preterm infants with a gestational age ranging from 26 to 35 weeks were diagnosed as having cystic PVL. The mean day of diagnosis of periventricular echodensities was 3 ± 2 days (range 1–11 days), and of cystic PVL 21 ± 8 days (range 2–47 days). Of 79 infants (1988–1997) eligible for neurodevelopmental follow-up (91%), hemi-, di-, or tetraplegia was diagnosed in 61 (77%), normal mental outcome in 22 (28%), associated visual disorders in 41 (52%) and seizure disorders in 12 (15%) infants. Significant risk factors associated with the development of cystic PVL were premature rupture of membranes, chorioamnionitis, and hyperbilirubinaemia (odds ratios 4.665, 6.026, and 2.460 respectively). Subgroup analysis according to gestational age (26–28, 29–32, 33–35 weeks) revealed similar results despite spontaneous labour (26–28 weeks; odds ratio 4.808) and pre-eclampsia (33–35 weeks; odds ratio 3.517). Multiple pregnancy was associated with a twofold increased risk (odds ratio 2.075). The white matter damage probably accounted for the significantly higher prevalence of apnoeas (P < 0.001) and neonatal seizures (P < 0.001). Cysts located bilateral or parieto-occipital were associated with a higher risk of cerebral palsy (odds ratios 6.933 and 4.327 respectively). Solely anterior located cysts were associated with normal neurological outcome. Increasing size of the cysts was associated with increasing risk of cerebral palsy with a cut-off value of 10 mm (odds ratio 3.300 and above) and all infants with cysts of more than 20 mm diameter had cerebral palsy. Conclusion The high prevalence of premature rupture of the membranes and chorioamnionitis further supports the role of intra-uterine infection in the pathogenesis of periventricular leucomalacia. The overall prognosis of cystic periventricular leucomalacia is poor. Received: 30 September 1999 and in revised form: 28 February 2000 / Accepted: 17 March 2000     

Reduction in periventricular haemorrhage in preterm infants.

Our previous cerebral ultrasound study of antecedents of periventricular haemorrhage in infants weighing 1250 g or less at birth suggested that neonatal events that caused increased or fluctuating cerebral blood flow lead to periventricular haemorrhage. As the risk period for this type of haemorrhage was the first four days of life strict guidelines were introduced to avoid the previously identified neonatal risk factors. No attempt was made to modify obstetric practice. Over the next two years, although the obstetric risk profile, the frequency and severity of hyaline membrane disease, and the gestation, birth weight, and sex distributions of a similar cohort of infants did not change, the incidence of periventricular haemorrhage decreased significantly from 60% to 36%. Significant antecedents of haemorrhage similar to those found in the previous study included severe bruising, low arterial:fractional inspiratory oxygen ratio and low packed cell volume on admission, hyaline membrane disease, hypercarbia, and hypoxaemia. Assisted ventilation, pneumothorax, treatment with tubocurarine, and hypotension were no longer significant risk factors for periventricular haemorrhage. A multivariate discriminant analysis correctly predicted haemorrhage in 86% of the study group when bruising, hypercarbia, hypoxaemia, hyaline membrane disease, and low gestation were considered. These results suggest that changes in neonatal practices can reduce the incidence of periventricular haemorrhage and that drug studies indicating similar reduction in haemorrhage need to be evaluated carefully to ensure that placebo and treated groups are in fact comparable.     

Perinatal factors, periventricular haemorrhage and mortality in very low birthweight infants

In a population of 225 very low birthweight infants born over a 21 month period the cerebroventricular system was scanned by ultrasound. One third of the infants developed a periventricular haemorrhage; in 41% of infants the haemorrhage was detected before an hour of age and 66% of all haemorrhages occurred within the first 24 hours. Statistically significant associations with periventricular haemorrhage included vaginal delivery, endotracheal intubation and intravenous sodium bicarbonate when this was administered in the first 24 hours. In a stepwise regression analysis, however, these and other potentially significant variables added little to the total accountable variance. A similar analysis of perinatal factors and mortality revealed that decreasing gestation was the major association with death.     

Perinatal factors, periventricular haemorrhage and mortality in very low birthweight infants

In a population of 225 very low birthweight infants born over a 21 month period the cerebroventricular system was scanned by ultrasound. One third of the infants developed a periventricular haemorrhage; in 41% of infants the haemorrhage was detected before an hour of age and 66% of all haemorrhages occurred within the first 24 hours.
Statistically significant associations with periventricular haemorrhage included vaginal delivery, endotracheal intubation and intravenous sodium bicarbonate when this was administered in the first 24 hours. In a stepwise regression analysis, however, these and other potentially significant variables added little to the total accountable variance. A similar analysis of perinatal factors and mortality revealed that decreasing gestation was the major association with death.     

Brain ultrasonography in the premature infant

Brain ultrasonography plays a central role in the detection and management of neonatal disease in the preterm infant. Although morphological study, using high-frequency transducers, remains the cornerstone of imaging, pulsed and colour Doppler scans provide additional information and improve the diagnostic and prognostic accuracy of ultrasonography. Particular features of normal brain US in the extremely preterm infant are reported. Cerebral haemorrhage and its different patterns (intraventricular haemorrhage and periventricular hemorrhagic infarction) are described. The value of Doppler techniques is emphasized, e.g. demonstration of coloured signal within the aqueduct of Sylvius, visualization of patency of the terminal veins, demonstration of Doppler spectrum fluctuations, recognition of low blood flow, and the detection of vasodilatation. The sonographic diagnosis of periventricular leucomalacia and its difficulties are documented. Some uncommon brain lesions of the premature infant are illustrated, e.g. gangliothalamic ischaemic damage, cortical necrosis, focal infarcts, etc. The importance of repeating the US examinations until near term is highlighted.     

Magnetic resonance imaging at term and neuromotor outcome in preterm infants

In order to evaluate the value of neonatal brain magnetic resonance imaging (MRI) for predicting neuromotor outcome in very low birthweight (VLBW) preterm infants, 51 such infants with gestational age <34 wk underwent brain MRI at term age. Myelination, parenchymal lesions (haemorrhage, leukomalacia, infarction, reduction of white matter), parenchymal lesions without subependymal haemorrhage, ventricular/brain ratios and widths of the extracerebral spaces were assessed. The MRI findings were compared with cranial ultrasound (US) performed at term. Infants' neuromotor development was followed up until 18 mo corrected age. Parenchymal lesions seen in MRI at term predicted cerebral palsy (CP) with 100% sensitivity and 79% specificity, the corresponding figures for US being 67% and 85%, respectively.
Parenchymal lesions in MRI, excluding subependymal haemorrhages, predicted CP with a sensitivity of 82% and a specificity of 97%, the corresponding figures for US being 58% and 100%, respectively. Delayed myelination, ventricular/brain ratios and widths of the extracerebral spaces failed to predict CP. Term age is a good time for neuroradiological examinations in prematurely born high-risk infants. Parenchymal lesions seen in MRI are reliable predictors for CP.