Neonatal ventriculomegaly: Pathophysiology and management guided with cranial ultrasonography.

Neonatal ventriculomegaly often, but not always, follows intraventricular haemorrhage in infants born preterm. Serial cranial ultrasonography (CUS) is a very useful tool to evaluate the mechanism behind ventricular dilatation, to differentiate several types of cerebrospinal fluid retention, and to guide treatment. This review examines neonatal ventriculomegaly and its definition, pathophysiology, treatment, and prognosis from the perspective of CUS assessment. It also outlines the consensus statements formulated by the EurUS.Brain group, which are based on rounds of expert opinions on neonatal ventriculomegaly management, detailing the need and timing of ventricular access device placement, in the context of posthaemorrhagic ventricular dilation. The pathophysiology of neonatal ventriculomegaly is more complex than previously considered. CUS is a valuable, non-invasive tool to determine pathophysiology, intervention thresholds, and prognosis in neonates with ventriculomegaly. Given new insights into the existence of glymphatics and water circulation in the cerebrum, further research in that area may bring new treatment options.

Randomized Control Trial of Postnatal rhIGF-1/rhIGFBP-3 Replacement in Preterm Infants: Post-hoc Analysis of Its Effect on Brain Injury.

Background: Postnatal insulin-like growth factor-1 (IGF-1) replacement with recombinant human (rh)IGF-1 and IGF binding protein-3 (rhIGF-1/rhIGFBP-3) is being studied as a potential treatment to reduce comorbidities of prematurity. We have recently reported on a phase II, multicenter, randomized, controlled trial comparing postnatal rhIGF-1/rhIGFBP-3 replacement with standard of care (SOC) in extremely preterm infants (NCT01096784). Maximum severity of retinopathy of prematurity was the primary endpoint of the trial and presence of GMH-IVH/PHI one of the pre-specified secondary endpoints. Infants therefore received serial cranial ultrasound scans (CUS) between birth and term age. In this post-hoc analysis we present a detailed analysis of the CUS data of this trial and evaluate the effect of postnatal rhIGF-1/rhIGFBP-3 replacement on the incidence of different kinds of brain injury in extremely preterm infants. Methods: This report is an exploratory post-hoc analysis of a phase II trial in which infants <28 weeks gestational age were randomly allocated to rhIGF-1/rhIGFBP-3 or SOC. Serial cranial ultrasounds were performed between birth and term-equivalent age. Presence of germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH), periventricular hemorrhagic infarction (PHI), post-hemorrhagic ventricular dilatation, and white matter injury (WMI) were scored by two independent masked readers. Results: The analysis included 117 infants; 58 received rhIGF-1/rhIGFBP-3 and 59 received SOC. A trend toward less grade II-III GMH-IVH and PHI was observed in treated infants vs. SOC. A subanalysis of infants without evidence of GMH-IVH at study entry (n = 104) showed reduced progression to GMH-IVH in treated infants (25.0% [13/52] vs. 40.4% [21/52]; not significant). No effects of rhIGF-1/rhIGFBP-3 on WMI were observed. Conclusion: The potential protective effect of rhIGF-1/rhIGFBP-3 on the occurrence of GMH-IVH/PHI appeared most pronounced in infants with no evidence of GMH-IVH at treatment start.

Cranial ultrasound findings in preterm germinal matrix haemorrhage, sequelae and outcome.

Germinal matrix-intraventricular haemorrhage (GMH-IVH), periventricular haemorrhagic infarction (PHI) and its complication, post-haemorrhagic ventricular dilatation (PHVD), are still common neonatal morbidities in preterm infants that are highly associated with adverse neurodevelopmental outcome. Typical cranial ultrasound (CUS) findings of GMH-IVH, PHI and PHVD, their anatomical substrates and underlying mechanisms are discussed in this paper. Furthermore, we propose a detailed descriptive classification of GMH-IVH and PHI that may improve quality of CUS reporting and prediction of outcome in infants suffering from GMH-IVH/PHI.

Preterm white matter injury: ultrasound diagnosis and classification.

White matter injury (WMI) is the most frequent form of preterm brain injury. Cranial ultrasound (CUS) remains the preferred modality for initial and sequential neuroimaging in preterm infants, and is reliable for the diagnosis of cystic periventricular leukomalacia. Although magnetic resonance imaging is superior to CUS in detecting the diffuse and more subtle forms of WMI that prevail in very premature infants surviving nowadays, recent improvement in the quality of neonatal CUS imaging has broadened the spectrum of preterm white matter abnormalities that can be detected with this technique. We propose a structured CUS assessment of WMI of prematurity that seeks to account for both cystic and non-cystic changes, as well as signs of white matter loss and impaired brain growth and maturation, at or near term equivalent age. This novel assessment system aims to improve disease description in both routine clinical practice and clinical research. Whether this systematic assessment will improve prediction of outcome in preterm infants with WMI still needs to be evaluated in prospective studies.

State-of-the-art neonatal cerebral ultrasound: technique and reporting.

In the past three decades, cerebral ultrasound (CUS) has become a trusted technique to study the neonatal brain. It is a relatively cheap, non-invasive, bedside neuroimaging method available in nearly every hospital. Traditionally, CUS was used to detect major abnormalities, such as intraventricular hemorrhage (IVH), periventricular hemorrhagic infarction, post-hemorrhagic ventricular dilatation, and (cystic) periventricular leukomalacia (cPVL). The use of different acoustic windows, such as the mastoid and posterior fontanel, and ongoing technological developments, allows for recognizing other lesion patterns (e.g., cerebellar hemorrhage, perforator stroke, developmental venous anomaly). The CUS technique is still being improved with the use of higher transducer frequencies (7.5-18 MHz), 3D applications, advances in vascular imaging (e.g. ultrafast plane wave imaging), and improved B-mode image processing. Nevertheless, the helpfulness of CUS still highly depends on observer skills, knowledge, and experience. In this special article, we discuss how to perform a dedicated state-of-the-art neonatal CUS, and we provide suggestions for structured reporting and quality assessment.

A Novel Scoring System for Term-Equivalent-Age Cranial Ultrasound in Extremely Preterm Infants.

The role of term-equivalent-age (TEA) cranial ultrasound (cUS) in predicting outcome in preterm infants is increasingly being recognized. However, a detailed quantitative scoring system that allows comparison of groups and comparison with TEA magnetic resonance imaging (MRI) scoring systems is lacking. Eighty-four extremely preterm infants underwent cUS and MRI at TEA. Cranial US was evaluated using a novel detailed scoring system. Agreement between cUS and MRI scores was good (Spearman's ρ = 0.51, p < 0.001). Outcome at 30 mo corrected was assessed in 66 of 84 preterm and 85 term-born infants. Sensitivity was the same for cUS and MRI in prediction of cerebral palsy (75%) and severe cognitive delay (100%); the specificity was slightly higher for MRI (cerebral palsy: 97% vs. 90%, severe cognitive delay: 95% vs. 90%). The proposed novel cUS scoring system is a helpful tool in quantitative assessment of cUS at TEA and prediction of outcome at 30 mo.

A scoring system predicting the clinical course of CLPB defect based on the foetal and neonatal presentation of 31 patients.

Recently, CLPB deficiency has been shown to cause a genetic syndrome with cataracts, neutropenia, and 3-methylglutaconic aciduria. Surprisingly, the neurological presentation ranges from completely unaffected to patients with virtual absence of development. Muscular hypo- and hypertonia, movement disorder and progressive brain atrophy are frequently reported. We present the foetal, peri- and neonatal features of 31 patients, of which five are previously unreported, using a newly developed clinical severity scoring system rating the clinical, metabolic, imaging and other findings weighted by the age of onset. Our data are illustrated by foetal and neonatal videos. The patients were classified as having a mild (n = 4), moderate (n = 13) or severe (n = 14) disease phenotype. The most striking feature of the severe subtype was the neonatal absence of voluntary movements in combination with ventilator dependency and hyperexcitability. The foetal and neonatal presentation mirrored the course of disease with respect to survival (current median age 17.5 years in the mild group, median age of death 35 days in the severe group), severity and age of onset of all findings evaluated. CLPB deficiency should be considered in neonates with absence of voluntary movements, respiratory insufficiency and swallowing problems, especially if associated with 3-methylglutaconic aciduria, neutropenia and cataracts. Being an important differential diagnosis of hyperekplexia (exaggerated startle responses), we advise performing urinary organic acid analysis, blood cell counts and ophthalmological examination in these patients. The neonatal presentation of CLPB deficiency predicts the course of disease in later life, which is extremely important for counselling.

Volvulus in term and preterm infants - clinical presentation and outcome.

AIM: Our aim was to assess if term and preterm infants with volvulus showed different patterns with regard to pathogenesis, clinical presentation and outcome. METHODS: We reviewed the medical records and imaging data of infants aged less than six months with volvulus treated in a single surgical referral centre from 2006-2013. RESULTS: Volvulus was diagnosed in 19 infants, with no anatomical anomaly in three of the 12 preterm infants and one of the seven term infants. Most cases (74%) presented during the first eight days of life. Later presentations occurred exclusively in preterm infants, with only one of the five having no anatomic anomalies. Bilious vomiting was the leading symptom in six of the seven term infants, while the symptoms in preterm infants were rather nonspecific. Intestinal necrosis, with the need for bowel resection, occurred in one term (14%) infant and nine (75%) preterm infants. CONCLUSION: The clinical presentation and outcome of volvulus differed between preterm and term infants, but the rate and distribution of underlying anomalies did not differ. Symptoms in preterm infants were often nonspecific and led to a delay in diagnosis. This might have contributed to the higher rate of intestinal necrosis in preterm infants.

"New-generation" pulse oximeters in extremely low-birth-weight infants: how do they perform in clinical practice?

The aim of this study was to evaluate the performance of "new-generation" pulse oximeters in extremely low-birth-weight ([ELBW] ≤ 1000 g) infants. In a prospective crossover observational study, the performance of pulse oximeters of 3 brands (Masimo, Nellcor, and Philips) was evaluated by dual SpO2 measurement in ELBW infants. Disposable probes of either equal or different brands were placed around both feet of the patient simultaneously for approximately 4 hours. Probes were switched between feet every hour. Absolute differences in SpO2 values (ΔSpO2) and the bias between brands were studied. Nine ELWB infants were included (gestational age: mean ± SD = 26(3)/7 ± 1 4/7 weeks). The median (range) ΔSpO2 was 2% (0%-26%). In 9% of the time, ΔSpO2 was 5% or more. The variance of the difference of the 3 pulse oximeter brands was not significantly different. No consequent bias between brands was found. Simultaneously obtained pulse oximeter measurements from the feet of ELBW infants differ from each other. Our results suggest that it is not the brand but the handling of the pulse oximeter in clinical practice, such as the place and positioning of the probe, that influences the performance of the pulse oximeter the most. Improvement in the accuracy of oxygen-monitoring techniques for ELBW infants is required.

Neonatal magnetic resonance imaging and outcome at age 30 months in extremely preterm infants.

OBJECTIVE: To examine associations between brain white matter abnormalities, including diffuse excessive high signal intensities, detected on neonatal magnetic resonance imaging (MRI) with neurodevelopmental outcome at age 30 months. STUDY DESIGN: This was a prospective, population-based study of infants born at <27 weeks gestation (n=117) undergoing conventional MRI at term equivalent age (n=107). At age 30 months corrected, 91 of the preterm infants (78%) and 85 term-born controls were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). RESULTS: Cerebral palsy (CP) was present in 7% of the preterm group. On the BSID-III, mean composite scores were 96±9.5 for the cognitive scale, 97±14 for language scales, and 103±15 for motor scales, all within the normal range for age. Compared with the term-born controls, however, the preterm infants did not perform as well on all 3 scales, also when MRI was normal. Significant associations were seen between moderate to severe white matter abnormalities and CP (P<.001). The presence of diffuse excessive high signal intensities was not associated with performance on the BSID-III or with CP. CONCLUSION: This 3-year cohort of extremely preterm infants had low rates of major brain injury and impaired outcome. Neonatal MRI provides useful information, but this information needs to be treated with caution when predicting outcome.

Late germinal matrix hemorrhage-like lesions in very preterm infants.

In preterm infants, the germinal matrix is a common origin of hemorrhages during the first 7 days of life. Sonographically, germinal matrix hemorrhages present as subventricular echodensities evolving into pseudocysts. Similar lesions have been reported as incidental findings also beyond 7 days of life. They may result from vasculitis and ischemic infarction, rather than hemorrhage. To assess the occurrence, time course, and significance for neurodevelopment of such late germinal matrix hemorrhage-like lesions, we reviewed serial cerebral ultrasound examinations obtained in 86 sequentially admitted infants (gestational age <32 weeks or birth weight <1500 g). Neurodevelopment was assessed at 3 years (Bayley Scales of Infant Development). Nine infants had late isolated germinal matrix hemorrhage-like lesions. Their Psychomotor Development Index scores were significantly lower than that in infants without hemorrhage. Our results suggest that late isolated germinal matrix hemorrhage-like lesions are of clinical significance because of their notable incidence and association with neurodevelopmental outcome.

The clinical presentation of preterm cerebellar haemorrhage.

The objective of this study was to evaluate clinical symptoms and findings on cranial ultrasound (CUS) in preterm infants with cerebellar haemorrhage through retrospective analysis of all preterm infants with a postnatal CUS or MRI diagnosis of cerebellar haemorrhage admitted in a tertiary care centre between January 2002 and June 2009. Fifteen infants were identified; median gestational age was 25 2/7 weeks and median birth weight 730 g. We discerned six types of haemorrhage: subarachnoid (n = 3), folial (n = 1), lobar (n = 9, of which 4 bilateral), giant lobar (n = 1, including vermis) and contusional (n = 1). Especially in infants with lobar cerebellar haemorrhage, CUS showed preceding or concurrent lateral ventricle dilatation, mostly without intraventricular haemorrhage (IVH). Thirteen infants suffered from notable, otherwise unexplained motor agitation in the days preceding the diagnosis. In conclusion, motor agitation may be a presenting symptom of cerebellar haemorrhage in preterm infants. Unexplained ventriculomegaly can be a first sign of cerebellar haemorrhage and should instigate sonographic exploration of the cerebellum.

White matter changes in extremely preterm infants, a population-based diffusion tensor imaging study.

AIM: To investigate cerebral white matter (WM) abnormalities (J Pediatr 2003; 143: 171) and diffuse and excessive high signal intensities (DEHSI), (J Pediatr 1999; 135: 351) in a cohort of extremely preterm infants born in Stockholm during a 3-year period, using magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). METHODS: MRI at term-equivalent age was performed in 109 infants and DTI data were acquired in 54 infants. Survival rate in the entire cohort was 67%. Sixteen term-born healthy control infants were scanned for comparison. RESULTS: No or mild WM abnormalities were seen in 86% of infants and 14% had moderate or severe WM abnormalities. DEHSI were seen in infants with all grades of white matter abnormalities and were present in 56% of infants. In the WM at the level of centrum semiovale, infants with any WM abnormalities or DEHSI had lower Fractional Anisotropy and higher Apparent Diffusion Coefficient compared with control infants. No significant differences in diffusion were seen in infants without DEHSI compared with the controls in this region. Compared with controls, the preterm infants had significantly altered diffusion in the corpus callosum. CONCLUSION: Only 14% of the extremely preterm infants had moderate or severe WM abnormalities on MRI. However, the incidence of DEHSI was high. In the DEHSI regions, changes in diffusion parameters were detected, indicating altered WM organization.

Single-centre vs. population-based outcome data of extremely preterm infants at the limits of viability.

AIM: In response to the disappointing outcome data of the population-based EPICure study published in 2000, we compared the outcome of infants 22 0/7 to 25 6/7 weeks of gestational age (GA) in a single tertiary care centre 2000-2004 with that of EPICure. METHODS: EPICure tools and definitions, including 30 months' Bayley Scales. RESULTS: Of 83 infants <26 weeks born alive, more were admitted to intensive care--82% vs. 68% (p < 0.0001)--and more infants survived to discharge (57% vs. 26%, p < 0.0001; 69% vs. 39%, p < 0.01, of those admitted to intensive care). More infants, as a percentage of live births, survived without severe (41%, 34/83 vs. 20%, 233/1185, p < 0.0001) or overall disability (22%, 18/83 vs. 13%, 155/1185, p = 0.03). However, at the border of viability--GA 23 and 24 weeks--the rate of infants surviving without overall disability was not significantly higher (13%, 6/45 vs. 9%, 56/623). CONCLUSION: In infants <26 weeks of GA, increased rates of survival and survival without disability were observed in a single-centre inborn cohort born 5-8 years later than the EPICure cohort. This did not translate into increased survival without overall disability in infants of 23-24 weeks of GA.

The acoustic hood: a patient-independent device improving acoustic noise protection during neonatal magnetic resonance imaging.

BACKGROUND: Magnetic resonance imaging (MRI) is today the imaging modality of choice to investigate the neonatal brain. However, the acoustic noise during scanning is very loud, often exceeding 100 dBA. AIM: To reduce the acoustic noise during MRI for neonatal patients. If effective, this would create a safer environment and also result in fewer aborted examinations due to poor image quality from patient motion. METHODS: A passive acoustic noise protector, the acoustic hood, was built out of dampening material. Sound pressure measurements with and without the acoustic hood were performed using our clinical neonatal scan protocol, consisting of eight imaging sequences. The acoustic hood is placed over the newborn inside the MR scanner tunnel during the examination to absorb acoustic noise. RESULTS: The acoustic noise level was substantially reduced using the acoustic hood. Peak sound pressure was reduced 16.18-22.21 dBA depending on the pulse sequence. For the entire frequency spectra, reduction were between 4-13.59 dBA again varying with the pulse sequence. CONCLUSION: Acoustic noise can be reduced further than before by using the patient-independent acoustic hood in addition to other noise protection. We recommend the use of three passive hearing protections during neonatal MRI: (1) dental putty, (2) paediatric ear muffs, and (3) the acoustic hood.

Lateral ventricular size in extremely premature infants: 3D MRI confirms 2D ultrasound measurements.

Ventriculomegaly at term age is an important predictor of neurologic outcome in preterm infants. Previous studies have found only poor correlations between two-dimensional (2D) cranial ultrasound (US) measurements of lateral ventricles and volume measurements using three-dimensional (3D) magnetic resonance imaging (MRI). Paired cranial MRI and US scans in a population based cohort of 28 extremely preterm infants were obtained at term equivalent age. A 3D MRI volume and five different 2D ultrasound measurements were assessed for each lateral ventricle. Correlations and interobserver variability were calculated. Reliability of US measurements and correlations between MRI volumes and US measurements of the frontal horns and ventricular midbody were consistently good. The highest correlation was achieved by combining the coronal frontal horn measurements to a frontal horn product (r(2) = right 0.94, left 0.95). Our study underlines the value of cranial ultrasound measurements in neonatal care and follow-up.

Blood sampling via umbilical vein catheters decreases cerebral oxygenation and blood volume in preterm infants.

AIM: We have shown previously that blood sampling via umbilical artery catheters decreases cerebral oxygenation and cerebral blood volume in preterm infants. To evaluate alternative methods, we assessed the effects of blood sampling via umbilical vein catheters in a cohort of preterm infants. METHODS: Twenty neonates (median birth weight 900 g [range 410-1900 g], median gestational age 27 weeks [24-31 weeks]) were studied during routine blood sampling via umbilical vein catheters by near-infrared spectroscopy. Tissue oxygenation index and changes in concentrations of cerebral oxygenated and deoxygenated haemoglobin were measured and changes in cerebral oxygenation and cerebral blood volume were calculated. Oxygen saturation and heart rate were recorded simultaneously. RESULTS: There was a significant drop of cerebral oxygenation (-2.135 +/- 0.532 micromol/L) and cerebral blood volume (-0.037 +/- 0.019 mL/100 g tissue) during umbilical vein blood sampling. Although peripheral arterial oxygen saturation remained unchanged, cerebral tissue oxygenation index decreased from 64.8 +/- 2.5% to 62.4 +/- 2.6% (p < 0.01), accompanied by a slight increase in heart rate (from 140 +/- 2.9 to 144 +/- 2.9 beats/min, p < 0.01). CONCLUSIONS: Umbilical vein blood sampling reduces cerebral oxygenation and cerebral blood volume. The magnitude of the effects is similar to those during umbilical artery blood sampling.

Resting-state networks in the infant brain.

In the absence of any overt task performance, it has been shown that spontaneous, intrinsic brain activity is expressed as systemwide, resting-state networks in the adult brain. However, the route to adult patterns of resting-state activity through neuronal development in the human brain is currently unknown. Therefore, we used functional MRI to map patterns of resting-state activity in infants during sleep. We found five unique resting-states networks in the infant brain that encompassed the primary visual cortex, bilateral sensorimotor areas, bilateral auditory cortex, a network including the precuneus area, lateral parietal cortex, and the cerebellum as well as an anterior network that incorporated the medial and dorsolateral prefrontal cortex. These results suggest that resting-state networks driven by spontaneous signal fluctuations are present already in the infant brain. The potential link between the emergence of behavior and patterns of resting-state activity in the infant brain is discussed.