Brain Damage In Preterm Infants Research Articles

Depressed brainstem auditory electrophysiology in preterm infants after perinatal hypoxia–ischaemia

Our understanding of pathophysiology of hypoxic–ischemic brain damage in preterm infants remains very limited. We studied the amplitudes of brainstem auditory evoked response, recorded with 91–910/s clicks, at term in preterm infants after perinatal HI for functional status of the auditory brainstem. Compared with age-matched healthy preterm infants, the preterm infants after HI did not show any major abnormality in waves I and III amplitudes at any click rates. However, wave V amplitude was reduced significantly at 227 ( P < 0.05), 455 and 910/s (both P < 0.01). V/I amplitude ratio was slightly reduced at 455 and 910/s. Compared with normal term infants, waves III amplitude in the preterm infants after HI tended to be reduced at all click rates, and differed significantly the highest rate 910/s ( P < 0.05). Wave V amplitude was significantly reduced at higher click rates (455 and 910/s, P < 0.05 and 0.01). V/I amplitude ratio was slightly reduced at 455 and 910/s. The reduction of wave amplitudes generally became more significant with the increase in click rate. The slopes of III–V interval-rate function, and wave V amplitude–rate function were significantly steeper than in both the healthy preterm infants and the term infants. Thus, the major abnormality in the preterm infants after HI was a significant reduction in wave V amplitude that mainly reflects central auditory or brainstem function. Brainstem auditory electrophysiology is depressed and so brainstem auditory function is impaired in preterm infants after perinatal HI.

The assessment of visual acuity in children with periventricular damage: A comparison of behavioural and electrophysiological techniques

It has been controversial whether electrophysiology offers better precision than behavioural techniques in measuring visual acuity in children with brain damage. We investigated the concordance between sweep VEPs and Acuity Cards (AC) in 29 children with periventricular leukomalacia (PVL), the most common type of brain damage in preterm infants. An overall good correlation was shown but with relatively better behavioural acuity values. VEP/AC ratio was significantly correlated to corpus callosum posterior thinning. We propose that this result reflects the efficacy of the compensatory mechanisms following early brain damage which may differentially affect the two methods.

Inflammation at birth and the insulin‐like growth factor system in very preterm infants

Foetal inflammation is associated with an increased risk of brain damage in preterm infants whereas IGF-I is essential for cerebral development and exhibits anti-apoptotic properties. To assess levels of IGF-I and IGF binding proteins at very preterm birth and to evaluate their relationship with foetal pro-inflammation and cerebral damage. Levels of IGF-I, IGF binding protein 3 (IGFBP-3), high- (hp) and low-phosphorylated (lp) IGFBP-1 in cord blood and neonatal blood at 72 h after delivery were analysed in relation to levels of cytokines and cerebral damage as detected by ultrasound in 74 inborn infants [mean gestational age (GA) 27.1 weeks]. Evaluation was performed separately according to birth weight for GA. In cord blood of infants appropriate for gestational age (AGA) higher levels of IL-6 and IL-8 were associated with lower IGF-I (r =-0.38, p = 0.008 and r =-0.36, p = 0.014). Higher levels of IL-6, IL-8 and TNF-alpha were associated with both higher levels of lpIGFBP-1 (r = 0.54, p < 0.001, r = 0.50, p < 0.001 and r = 0.13, p = 0.012, respectively) and hpIGFBP-1 (r = 0.55, p < 0.001, r = 0.45, p = 0.002 and r = 0.32, p = 0.026, respectively). Infants with intraventricular haemorrhage grade III (n = 5) had higher levels of lp/hpIGFBP-1 in cord blood (p = 0.001 and 0.002, respectively). Pro-inflammation at birth is associated with changes in the IGF-system. This may be of importance for development of brain damage in preterm infants.

Circulating Interferon-gamma and White Matter Brain Damage in Preterm Infants

Circulating Interferon-gamma and White Matter Brain Damage in Preterm Infants

Magnesium sulfate exposure increases fetal blood flow redistribution to the brain during acute non-acidemic hypoxemia in goats

Background It is still controversial that intrapartum exposure to magnesium may or may not reduce brain damage in premature infants in human and animal models. Aims We investigated the effect of hypoxemia alone under magnesium exposure on fetal cardiovascular changes in chronically catheterized goat fetuses. Study design We performed a 3-day experimental protocol with control (10% glucose) on day 1, recovery on day 2, and magnesium on day 3. Magnesium sulfate was directly infused to fetuses in a bolus dose of 270 mg/kg followed by 80 mg/kg/h. Hypoxemia was induced by maternal inhalation of nitrogen gas on day 1 and on day 3. Cerebral blood flow was measured by colored microsphere techniques. Repeated measure ANOVA and Bonferroni's/Dunn's test were used for comparison. Subjects Six Japanese Saanen goats at 0.85 gestation. Outcome measures Fetal heart rate, blood pressure, and cerebral blood flow. Results Ionized magnesium concentrations were significantly increased. Fetal PO 2 decreased significantly from 30 mmHg to 14 mmHg without acidemia. Magnesium exposure significantly attenuated hypoxemia-induced bradycardia but did not affect blood pressure. Hypoxemia significantly increased fetal brain blood flow from the pre-hypoxic levels on day 1. Magnesium exposure further increased hypoxemia-induced brain blood flow on day 3, but statistical significance was limited to the cerebral cortex. Conclusion In near-term, initially healthy goat fetuses, brain blood flow during acute hypoxemia was significantly increased with magnesium sulfate exposure.

Circulating Interferon-gamma and White Matter Brain Damage in Preterm Infants

The fetal inflammatory response has been suggested as causal in neonatal morbidity. Serial levels of circulating cytokines were evaluated in 74 infants with a mean gestational age (GA) of 27.1 wk. Pro-inflammatory [tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), IL-1 beta, IL-2, IL-6, IL-8, IL-12] [corrected] and modulatory (IL-4, IL-10) cytokines were analyzed from cord blood, and at 6, 24 [corrected] and 72 h postnatal age. Measure of cytokine burden over time was assessed by calculating the area under curve (AUC) for analyzed levels (0-72 h). Premature rupture of membranes (PROM) was associated with higher levels of IL-2 at birth and at 6 h, of IFN-gamma at 6 and 24 h postnatal age and of TNF-alpha at 6 and 24 h. Levels of IFN-gamma at 6, 24, and 72 h were increased in infants developing white matter brain damage (WMD) compared with those without WMD. Infants with arterial hypotension requiring dopamine treatment had an increase in IL-6 with a peak at 6 h of age. Severe intraventricular hemorrhage (IVH) was associated with increase in AUC [(IL-6) and (IL-8), odds ratio (OR) 2.8 and 13.2 respectively], whereas white matter brain damage (WMD) [corrected] was associated with increase in AUC (IFN-gamma; OR, 26.0) [corrected] A fetal immune response with increased postnatal levels of IFN-gamma was associated with development of WMD. PROM was associated with a T-helper 1 cytokine response with increased levels of IFN-gamma. Type of inflammatory response appears of importance for subsequent morbidity.

Ontogeny of AMPA and NMDA receptor gene expression in the developing sheep white matter and cerebral cortex

This study examined the hypothesis that the high prevalence of white matter injury in premature infants is associated with increased expression of calcium-permeable forms of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of glutamate receptors in pre-myelinating white matter. We characterized expression of subunits of the AMPA, and for reference, the N-methyl- d-aspartate (NMDA), glutamate receptors at 0.5, 0.65, 0.85, and term gestation in the ovine fetal white matter and cerebral cortex. There was a low expression of the critical calcium-impermeable AMPA receptor GluR2 subunit in subcortical white matter both absolutely and relative to other AMPA subunits throughout gestation. In contrast, GluR2 subunit mRNA expression fell in the cerebral cortex with increasing gestation whereas protein expression increased. These findings suggest a vulnerability of subcortical white matter to AMPA receptor-mediated calcium toxicity throughout the second half of gestation. Thus, the hypothesis that AMPA receptor-mediated glutamate toxicity contributes to brain damage in premature infants needs to be revised.

Electroencephalography and brain damage in preterm infants

Electroencephalography (EEG) is a sensitive method for detection of brain injury in preterm infants. Although the acute and chronic EEG changes are mainly non-specific regarding type of damage, they correlate with later neurological and cognitive function. In infants developing brain white matter damage, acute EEG findings include depression of background activity and presence of epileptic seizure activity. The chronic EEG changes associated with white matter injury and abnormal neurological development include delayed maturation, and presence of abundant Rolandic sharp waves. Cognitive limitations in preterm infants have been associated with changes in various sleep measures in EEG's recorded at full term. Continuous EEG-monitoring during neonatal intensive care shows that cerebral electrical activity during this vulnerable period can be affected by several extracerebral factors, e.g. cerebral blood flow, acidosis and some commonly used medications. For diagnosis of brain damage in preterm infants with neurophysiological methods, a combination of early continuous EEG monitoring during the initial intensive care period and full EEG, performed at later stages, is probably optimal.

The Role of the Intrauterine and Perinatal Environment in Cerebral Palsy

Author Disclosure Drs Paneth, Korzeniewski, and Hong did not disclose any relationships relevant to this article. After completing this article, readers should be able to: 1. Discuss the prevalence of cerebral palsy (CP) in school-aged children. 2. Describe the role of neuroimaging in CP. 3. Describe the impact of ventilatory practices in low-birthweight infants on the risk of CP. 4. Delineate the role of infection and fetal inflammation in pregnancy in the development of CP. The special importance of CP to clinicians whose practices encompass pregnancy and the perinatal or neonatal period is that no other neurodevelopmental disorder bears as close a causal relationship to the hazards of intrauterine and perinatal life. Although the strength of that relationship has been exaggerated at times, especially in relation to obstetric trauma and birth asphyxia, there can be no serious doubt that adverse events in pregnancy and the perinatal period do occasionally damage the fetal or neonatal brain. A distinctive feature of brain damage produced between early gestation and infancy is destruction of cerebral white matter or extrapyramidal tracts, thereby producing a clinical syndrome in which disturbance of motor control is a prominent and probably a necessary feature. Depending on the nature and extent of the insult, the motor disorder may be predominantly spastic, dyskinetic, or ataxic and may involve all four limbs (quadriplegia), one side (hemiplegia), or be most prominent in the legs (diplegia). CP severe enough to be recognized as a disability is found in about 1 in 500 school-age children in most developed countries, with little variation between countries or over the past 30 years. (1) Because CP often is accompanied by other neurodevelopmental disabilities, particularly seizure disorders, varying degrees of mental retardation, blindness, or deafness, affected children constitute the single largest group of children in the population who have major disabilities. (2) More …

218 Temporal Profile of Cytokines in Preterm Infants - IL-6 and IL-8 are Associated with Arterial Hypotension Whereas Interferon-Ã is Increased in White Matter Brain Damage

Background: Antenatal inflammation elicits a fetal inflammatory response which has been suggested causal in acute neonatal and chronic neurological morbidity. Knowledge of temporal changes in levels of proinflammatory and modulatory cytokines during the transition from fetal to neonatal life may improve understanding of the possible relationship between inflammatory response, circulatory impairment and subsequent brain damage in preterm infants. Objective: To evaluate temporal profiles of proinflammatory and modulatory cytokines in fetal and neonatal blood and determine their relationship to arterial hypotension and morphological brain damage in preterm infants.

Historical Perspectives

This month’s Historical Perspective is written by Osmund Reynolds. When I requested a personal reminiscence of how his research and article on detection of brain damage in preterm infants via cranial ultrasonography originated, I asked that he include the setting in which this advance occurred. His entertaining response provides a perspective on the evolution of neonatal care at University College Hospital (UCH), London. This recollection of the introduction of neonatal care at UCH is included in Part 1; part 2 focuses on the more specific introduction of cranial ultrasound imaging. It should be mentioned that the pace of development of neonatal intensive care in the United Kingdom generally was much slower than in the United States and some other countries. Indeed, in 1980, there were only 12 neonatal consultant posts for the entire UK. It is generally recognized that UCH was one of the leaders in this arena not only for the UK, but also for the world. For a more detailed discussion of the development of intensive care in the UK, the reader is referred to one in a series of “Witness Seminars” developed by the Wellcome Institute for the History of Medicine, for which Professor Reynolds was the major consultant. (1) 1. ↵ Origins of neonatal intensive care in the UK. In: Christie DA, Tansey EM, eds. Wellcome Witnesses to Twentieth Century Medicine. Vol.9 . London, United Kingdom: Wellcome Trust;2001 :1–75. [OpenUrl][1] # {#article-title-2} ### Introduction I first became interested in perinatal medicine in 1955 while undertaking a physiology BSc degree at St. Thomas’ Hospital Medical School in London. The head of the department was Professor Henry Barcroft (son of Sir Joseph), and Maureen Young was a lecturer. She taught me to measure blood gases using the Roughton-Scholander syringe; duplicate samples took about three quarters of an hour. After qualifying in medicine, I became a house physician on Professor Peter Sharpey-Shafer’s adult medical unit, which was an extremely stimulating environment with a very strong group of physiologically orientated investigators. Steve Semple taught … [1]: {openurl}?query=rft.jtitle%253DWellcome%2BWitnesses%2Bto%2BTwentieth%2BCentury%2BMedicine.%2B%26rft.volume%253D9%26rft.spage%253D1%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx

INTERNATIONAL SCHOOL OF NEUROLOGICAL SCIENCES, 13th Annual Symposium of the Child Neurology Section, Venice, Italy, September 13, 2003

The International School of Neurological Sciences, located on the island of San Servolo, Venice, Italy, was first founded in 1990 at the beginning of the Decade of the Brain. The school is divided into sections that meet periodically. Invited speakers are known worldwide for their work in the field of the neurologic sciences. Dr Paolo Curatolo (Rome) is the chairman of the Child Neurology Section, and he has always devoted great effort to the organization of international courses and workshops on challenging topics. The 13th Annual Symposium is entitled “Brain Damage in Preterm Infants: Causes and Consequences.”

Serial Protein S-100 Serum Levels in Preterm Babies with Perinatal Asphyxia and Periventricular White Matter Lesions

In the last years new diagnostic technologies were developed to assess brain development and to identify early brain injury. Some of them are very attractive methods but invasive, expensive, and time-consuming. The availability of clinically useful serum markers of risk for perinatal brain damage will easily permit the development of rational strategies for prevention of cerebral insults in neonates and more accurate prognostic counseling. In this study, protein S-100 (PS-100), a cytosolic constituent of neuroglial cells, was measured serially, during the neonatal period, in a group of preterm infants suffering perinatal asphyxia. Protein S-100 was measured at 1, 7, and 21 days of life by radioimmunoassay. Cerebral ultrasound confirmed cerebral white matter insult. The results of this study show significantly higher protein S-100 serum levels in asphyxiated preterm babies with periventricular white matter lesions, with a peak at 24 hours of life (5.7 +/- 2.9 microg/L) compared with healthy preterm babies (0.6 +/- 0.3 microg/L) ( p <0.05) and progressively lower values at seven (3.3 +/- 2.4 microg/L) and 21 days (2.2 +/- 1.3 microg/L) of life ( p <0.05). These data suggest that elevated protein S-100 serum levels can be considered an indicator of regional brain damage in preterm infants, allowing noninvasive, superior scrutiny of perinatal asphyxia and potential early preventive strategies.

Neonatal EEG: a powerful tool in the assessment of brain damage in preterm infants.

Serial EEG recordings beginning immediately after birth are not only of great diagnostic and prognostic value but also useful to elucidate the timing and the mode of brain injuries in the preterm newborn. It is extremely useful to distinguish between acute stage and chronic stage EEG abnormalities. The former is characterized by findings of acute depression such as increased discontinuity, decreased faster frequency activities, and lowered amplitudes. The latter mainly includes dysmature patterns and disorganized patterns. The timing of brain insult can be assessed by considering EEG findings in relation to the time of birth. Different modes of brain injury are associated with different types of EEG abnormalities and different types of neurological outcome. Sudden strong brain insults are usually associated with findings of severe depression followed by disorganized pattern and later cerebral palsy, while persistent mild insults are usually associated with prolonged mild depression followed by dysmature pattern and later mental retardation. Routine serial EEG studies in preterm infants demonstrated that one fourth of cerebral palsies in these infants were of antenatal origin, two thirds of perinatal origin and postnatal injuries played the least role. Periventricular leucomalacia (PVL) manifesting itself on the ultrasound in the late neonatal period and suggesting postnatal origin was often found to be of antenatal origin with an EEG soon after birth. PVL without apparent causes was often associated with abnormal fetal heart rate patterns and early neonatal EEG abnormalities, and considered to have originated in the antepartum period.

QUANTITATIVE T2 MRI STUDY OF BRAIN INJURIES IN PRETERM INFANTS: CORRELATION WITH NEURODEVELOPMENTAL OUTCOME. † 1030

Background: brain sonography(U.S) is currently the reference screening method for early detection of periventricular leukomalacia (PVL) and periventricular haemorrhage (PVH).During the neonatal period, MRI assesment of brain damage is difficult because of brain immaturity (unmyelinisation and brain water content). Aims: 1) to achieve a quantitative T2 MRI mapping (T2 map) of brain damage in premature infants during the neonatal period 2) to compare U.S, qualitative MRI (T2 weighted) and T2map findings to outcome at 18 mo of age. Methods:20 preterm babies, 26-33 weeks of gestation (mean 29) were studied at 37 wks conceptionnal age. MR scans were performed with a Brucker 2.35 Tesla. Spin-echo T2-weighted transverse scans were acquired using 3000ms/30,60,90,120,150 ms/2(TR/TE/Nex). Qualitative analysis of the MRI were performed on the fifth echo(TE=50ms) and on the T2map. Neurologic outcome was assesed using the Griffith test. Results:the table lists the T2map values in the periventricular white matter (w.m).For babies with good outcome, T2map increased from occipital to frontal region (normal myelination progress). For the babies with bad outcome T2map values were higher in the parietal and occipital regions.

Loss of CO 2 reactivity of cerebral blood flow is associated with severe brain damage in mechanically ventilated very low birth weight infants

Background: Early detection of pathophysiological factors associated with permanent and severe brain damage in preterm infants requiring intensive care is a major issue in neonatal neurology. The aim of this study was to investigate if an abnormal CO 2 reactivity of cerebral blood flow in high risk very low birth weight infants is associated with severe brain injury demonstrated at autopsy or by neurodevelopment examination at 18 months. Methods: The CO 2 reactivity of cerebral blood flow (xenon-133) was measured in 18 mechanically ventilated, severely ill, very low birthweight infants (gestational age 26–32 weeks, birthweight: 630–1360g) during the first 36 hours of life. Cerebral outcome was assessed on autopsy findings (n = 8) or at the age of 18 months using Bayley developmental scales (n = 10) Results: Eight infants with normal development at 18 months (within mean ± 2.5 SD of reference group) and two infants with normal cerebral autopsy findings had a median CO 2 reactivity of 24.4%/kPa CO 2 (interquartile range 14.7–41.2). Two infants with abnormal development (> 2.5 SD below mean) and six infants with hypoxic-ischaemic encephalopathy at autopsy had a median CO 2 reactivity of 3.4%/kPa CO 2 (interquartile range 8.0–11.7). Conclusion: In mechanically ventilated very low birthweight infants low CO 2 reactivity of cerebral blood flow (below 10%/kPa CO 2) during the first 36 hours of life was associated with poor neurodevelopmental outcome or hypoxicischaemic encephalopathy at autopsy. Loss of CO 2 reactivity may play a role in the pathogenesis of hypoxic ischaemic encephalopathy. It is a candidate for predicting early severe brain damage in preterm infants requiring intensive care and for controlling the effect of early interventions.

Mechanical Ventilation in Preterm Infants

GRAZIANI, L. J.; SPITZER, A. R.; MITCHELL, D. G.; MERTON, D. A.; STANLEY, C.; ROBINSON, N.; McKEE, L.Author Information

Mechanical Ventilation in Preterm Infants: Neurosonographic and Developmental Studies

Surviving preterm infants of less than 34 weeks' gestation who were selected on the basis of serial cranial ultrasonographic findings during their nursery course had repeated neurologic and developmental examinations during late infancy and early childhood that established the presence (n = 46) or absence (n = 205) of spastic forms of cerebral palsy. Of the 205 infants without cerebral palsy, 22 scored abnormally low on standardized developmental testing during early childhood. The need for mechanical ventilation beginning on the first day of life (n = 92) was significantly related to gestational age, birth weight, Apgar scores, patent ductus arteriosus, grade III/IV intracranial hemorrhage, large periventricular cysts, and the development of cerebral palsy. In the 192 mechanically ventilated infants, vaginal bleeding during the third trimester, low Apgar scores, and maximally low PCO2 values during the first 3 days of life were significantly related to large periventricular cysts (n = 41) and cerebral palsy (n = 43), but not to developmental delay in the absence of cerebral palsy (n = 18). The severity of intracranial hemorrhage in mechanically ventilated infants was significantly associated with gestational age and maximally low measurements of PCO2 and pH, but not with Apgar scores or maximally low measurements of PO2. Logistic regression analyses controlling for possible confounding variables disclosed that PCO2 values of less than 17 mm Hg during the first 3 days of life in mechanically ventilated infants were associated with a significantly increased risk of moderate to severe periventricular echodensity, large periventricular cysts, grade III/IV intracranial hemorrhage, and cerebral palsy. Neurosonographic abnormalities were highly predictive of cerebral palsy independent of PCO2 measurements.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral magnetic resonance imaging (MRI) of very low birth weight infants at one year of corrected age.

Cerebral MRI was performed at 1.5 T in 27 infants with birth weight below 1500 grams at 1 year of corrected age. The images were compared to those reported on normal development at the same age. On T1 weighted images, 20 (74.1%) of the 27 infants showed myelin deposition different from what has been reported to be normal. Areas most affected were the central occipital white matter and the centrum semiovale. Both correspond to "watershed areas" known to be at risk for periventricular leukomalacia in preterm infants. T2-weighted images showed delayed myelination in the same areas as described for T1. In addition, two infants showed delayed myelination in the central occipital white matter and one in the centrum semiovale. Patchy focal abnormalities involving the white matter were seen in seven (25.9%) infants. Mild cerebral atrophy, mainly of the cortex was found in 10 (37.0%) infants. Irregular shape of the lateral ventricles, especially of the occipital horns was present in 12 infants (44.4%). 11 of these infants also had deviating changes in myelination. Only 2 infants (7.4%) had a normal MRI examination. Follow-up MRI examinations are needed to determine whether the high percentage of changes in myelination represent delayed development or brain damage in preterm infants.