Ultrasound detection of white matter injury in very preterm neonates: practical implications

DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY ORIGINAL ARTICLE Ultrasound detection of white matter injury in very preterm neonates: practical implications GERDA VAN WEZEL-MEIJLER 1 | FRANCISCA T DE BRU°NE 2 | SYLKE J STEGGERDA 1 | ANNETTE VAN DEN BERG-HUYSMANS 2 | SIJME ZEILEMAKER 1 | LARA M LEIJSER 1 | JEROEN VAN DER GROND 2 1 Department of Paediatrics, Subdivision of Neonatology, Leiden University Medical Center, Leiden, The Netherlands. 2 Department of Radiology, Subdivision of Neuroradiology, Leiden University Medical Center, Leiden, The Netherlands. Correspondence to Dr G van Wezel-Meijler, Department of Paediatrics, Subdivision of Neonatology, J6-S, PO Box 9600, 2300 RC Leiden, the Netherlands. E-mail: G.van_Wezel-Meijler@lumc.nl PUBLICATION DATA AIM Diffuse white matter injury is not well detected by cranial ultrasonography (CUS). The aim of Accepted for publication 28th February 2011. this study was twofold: (1) to assess in very preterm neonates the predictive values of individual CUS abnormalities for white matter injury on MRI and neurological outcome; (2) to develop a strategy optimizing CUS detection of white matter injury. METHOD Very preterm neonates (n=67; 44 males, 23 females) underwent serial CUS and single MRI. Predictive values of CUS findings for a white matter classification on MRI, individual MRI findings, and neurological outcome at 2 years corrected age were calculated. The effects of timing and frequency of CUS were evaluated. RESULTS Periventricular echodensities (PVEs) predicted abnormal white matter on MRI, but absence of PVEs did not predict absence of white matter changes. Peri- and intraventricular haemorrhage (P ⁄ IVH) was highly predictive of abnormal white matter on MRI. Frequency and timing of CUS did not influence predictive values. P ⁄ IVH and abnormal ventricular size ⁄ shape were reasonably predictive of unfavourable outcome, whereas absence of CUS abnormalities predicted a favorable outcome. INTERPRETATION (1) If PVEs are present, there is a significant chance of abnormal white matter on MRI. (2) Increasing frequency of CUS does not increase its diagnostic performance for white matter injury. (3) P ⁄ IVH is highly predictive of abnormal white matter on MRI and reasonably predictive of unfavourable outcome. (4) Absence of PVEs and P ⁄ IVH on CUS does not guarantee normal white matter, but predicts a favourable outcome. ABBREVIATIONS CUS Cranial ultrasonography DEHSI Diffuse excessive high signal intensity NPV Negative predictive value PPV Positive predictive value PVEs Periventricular echodensities P ⁄ IVH Peri- and intraventricular haemorrhage PWMLsPunctate white matter lesions TEA Term-equivalent age White matter injury is one of the most frequently occurring forms of brain injury in infants born very preterm (gestational age<32wk). During recent decades, the character of white matter injury has shifted from ‘classic periventricular leukomalacia’ to more subtle or diffuse white matter injury. The latter, occurring in more than 80% of infants born very preterm, cannot be reliably diagnosed by ultrasonography.1–4 On T2weighted magnetic resonance imaging (MRI), it is assumed to be represented by areas of altered signal intensity throughout the white matter, so-called diffuse excessive high signal intensity (DEHSI) (Fig. 1) and by focal signal intensity changes, socalled punctate white matter lesions (PWMLs)4–6. PWMLs are better visualized on T1-weighted MRI (Fig. 2). Although MRI is increasingly used in neonates and has proved safe and reliable to detect various forms of neonatal brain injury, it is not suitable for repetitive examinations.7,8 Therefore cranial ultrasonography (CUS) is still the preferred modality for serial neuroimaging during the neonatal period.9 In this perspective it is important to develop a CUS screening system, enabling optimal detection of white matter injury and selection of neonates needing MRI. A recent study, considering MRI as the criterion standard, showed a good reliability of CUS in very preterm infants with severely abnormal white matter. However, CUS was less reliable in demonstrating mild and moderate white matter abnormalities.4 In that study, CUS and MRI classifications of white matter injury were introduced, based on respectively echogenicity- and signal-intensity changes in the white matter and on loss of white matter volume. However, we did not test the performance of individual CUS findings for predicting white matter injury and did not analyse the influence of frequency and timing of CUS examinations on the reliability of CUS. Early detection of brain injury may be important for timely intervention in high-risk neonates. With the present study we aimed to develop a strategy to optimize CUS detection of white matter injury, focusing on specific CUS findings and on the number and timing of CUS examinations. We hypothesized that specific CUS findings, including inhomogeneous and grade 2 periventricular echodensities (PVEs), are predictive of white matter injury on MRI.10 In addition we hypothesized, ª The Authors. Developmental Medicine & Child Neurology ª 2011 Mac Keith Press DOI: 10.1111/j.1469-8749.2011.04060.x 29 Figure 1: T2-weighted magnetic resonance image in very preterm infant, Figure 2: T1-weighted magnetic resonance image in very preterm infant, scanned at term-equivalent age, showing diffuse excessive high signal scanned around term-equivalent age, showing bilateral, multiple, conflu- intensity in the frontal and occipital white matter (arrows). The figure also ent punctate white matter lesions (arrows) in the central white matter. shows mildly dilated and abnormally shaped lateral ventricles. based on the results of former studies, that PVEs on CUS predict DEHSI on MRI and that increasing the number of CUS examinations increases the reliability of CUS for detecting white matter injury.10,11 The specific aims were to assess the predictive values of individual CUS findings for (1) the white matter classification on MRI, (2) individual MRI findings, and (3) neurological outcome at 2 years corrected age; we also assessed whether (4) increasing the number of CUS examinations increases the reliability of CUS for detecting white matter injury, and (5) timing of CUS examinations influences the reliability of CUS for detecting white matter injury. METHOD Participants Between May 2006 and October 2007 eligible infants, born very preterm and admitted to our tertiary neonatal unit, were included in a neuroimaging study, comprising serial CUS, according to the standard of care for these neonates9 and a single MRI, preferably performed around term-equivalent age (TEA). The study was approved by the Medical Ethics Committee and informed consent was obtained from the parents. Results on prevalence of CUS and MRI abnormalities and on prediction of white matter injury by CUS, based on the white matter classification, were published elsewhere.1,4,12 CUS CUS examinations were performed within 24 hours of birth, thereafter at least weekly until discharge or transfer to another 30 Developmental Medicine & Child Neurology 2011, 53 (Suppl. 4): 29–34 hospital and again around TEA, on the same day as the MRI, according to a standard protocol.9 All CUS examinations were assessed by LML and GvW-M or LML and SJS, focusing on individual CUS findings. The following echogenicity changes in the white matter were recorded: non-physiological PVEs, cystic lesions (small and localized or more extensive), and focal white matter echodensity presenting periventricular hemorrhagic infarction. The appearance of PVEs (homogeneous, inhomogeneous, and grades 1 or 2) was noted.11 In addition, peri- and intraventricular haemorrhages (P ⁄ IVH), grades 1 to 3 according to the classification of Volpe13, and the size and shape of the lateral ventricles were recorded. The latter were only done for the CUS examination performed around TEA. The size and shape of the ventricles were visually scored as normal ⁄ mildly abnormal, moderately abnormal, and severely abnormal. MRI MRI examinations were performed according to a standard protocol for imaging the newborn infant’s brain, using a 3.0T magnetic resonance system (Philips Medical Systems, Best, the Netherlands) as recently described.7 In summary, scans included at least three-dimensional T1-weighted gradient echo MRI (repetition time ⁄ echo time 9.7 ⁄ 4.6ms, flip angle 8), T2-weighted TSE MRI (repetition time ⁄ echo time 6269 ⁄ 120ms, turbofactor 18), diffusion-weighted images in three directions (repetition time ⁄ echo time 2406 ⁄ 64ms), and T2* susceptibility-weighted MRI (repetition time ⁄ echo time 735 ⁄ 16ms) in the transverse plane. All MRI examinations were assessed by LML and FTdB or by SJS and FTB, who were blinded to the CUS findings. For this part of the study the T1- and T2-weighted images were assessed. Particular attention was paid to the white matter by using a recently described classification to score the grade of white matter injury. In summary, the white matter was scored as normal or mildly abnormal if no signal intensity changes or only homogeneous DEHSI and ⁄ or few (£6) PWMLs were seen and if the shape and size of the lateral ventricles were normal or only mildly abnormal. A moderately abnormal white matter score was applied if multiple (>6) PWMLs, and ⁄ or small localized cystic lesions, and ⁄ or inhomogeneous DEHSI, and ⁄ or moderately abnormal lateral ventricles were seen. The white matter was scored as severely abnormal in the case of more serious abnormalities.4 Table I: General characteristics and ultrasound findings of the total group included and group with magnetic resonance imaging (MRI) at postmenstrual age <44wk General characteristics Patients included Males (%) Mean weight at birth (g) (range) Mean GA (wk) (range) Mean postmenstrual age at MRI (wk) (range) MRI findings Normal ⁄ mildly abnormal WM (%) Moderately ⁄ severely abnormal WM (%) DEHSI (%) >6 PWMLs (%) CUS findings PVEs (%) Grade 2 PVEs (%) Inhomogeneous PVEs (%) Duration PVEs>14d (%) P ⁄ IVH grade 1–2 (%) P ⁄ IVH grade 3 (%) Abnormal size and ⁄ or shaped ventricles (%) Total group Postmenstrual age at MRI <44wk 108 67 (62) 1205.7 (585–1960) 67 44 (66) 1228.2 (585–1960) 29.0 (25.6–31.9) 44.9 (39.1–62.1) 28.9 (25.6–31.2) 42.5 (39.1–44.0) 26 (24) 18 (27) 82 (76) 49 (73) 76 (70) 18 (17) 59 (88) 13 (19) 87 (81) 11 (10) 72 (67) 43 (40) 23 (21) 8 (7) 56 (52) 55 (82) 8 (12) 46 (69) 29 (43) 15 (22) 4 (6) 28 (42) DEHSI, diffuse excessive high signal intensity; PWMLs, punctate white matter lesions; CUS, cranial ultrasonography; PVEs, periventricular echodensities; P ⁄ IVH, peri- and intraventricular haemorrhage; WM, white matter. Follow-up Around 2 years of age, the infants were seen by an experienced neonatologist for clinical follow-up. The children underwent a standardized neurological examination to assess the presence of cerebral palsy (CP) or abnormal muscular tone. Cognitive and psychomotor development was assessed using the Dutch version of the Bayley Scales of Infant Development. A mental developmental index score and a psychomotor developmental index score were calculated for the corrected age. A score of ‡1 SD below the normative mean was defined as a developmental delay. Statistical methods First, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of individual CUS findings (presence, aspect, duration and grade of PVEs; focal white matter echodensity; P ⁄ IVH; and shape and size of the lateral ventricles on the CUS performed around TEA) for the MRI white matter classification were calculated. Secondly, predictive values of PVEs on CUS for DEHSI on MRI and of inhomogeneous PVEs on CUS for PWMLs on MRI were calculated. In addition, to explore whether increasing the number of CUS examinations improved the predictive value of CUS for MRI, the predictive values of PVEs present on the first CUS examination and also respectively on any CUS performed during the first week, first 2 weeks, or first 4 weeks of life were Table II: Predictive values of individual ultrasound findings for white matter classification on magnetic resonance imaging (MRI), of periventricular echodensities (PVEs) for diffuse excessive high signal intensity (DEHSI)a, and of inhomogeneous PVEs for punctate white matter lesions (PWMLs)b for the group of patients with MRI at postmenstrual age <44wk (n=67) CUS finding PVEs Inhomogeneous PVEs Grade 2 PVEs Duration>14d P ⁄ IVH grade 3 P ⁄ IVH grade 1–3 Size and shape of ventricles White matter classification on MRI PPV NPV Sensitivity Specificity 82 (71–92) 67 (54–80) 14 (4–24) 47 (33–61) 8 (0–16) 35 (21–48) 55 (41–69) 17 (0–34) 28 (7–48) 94 (84–100) 67 (45–88) 100 (96–100) 89 (74–100) 94 (84–100) 73 (61–85) 72 (59–85) 88 (65–100) 79 (65–94) 100 (82–100) 90 (76–100) 96 (90–100) 25 (1–50) 24 (6–42) 29 (17–40) 32 (17–46) 29 (17–40) 33 (20–47) 44 (28–59) 13 (0–35) 32 (19–44) 87 (78–96) 20 (8–31) 8 (0–24) 81 (64–98) DEHSI and PWMLs on MRI a PVEs Inhomogeneous PVEsb 81 (71–91) 69 (44–94) Numbers between brackets indicate the 95% confidence intervals for these indices. CUS, cranial ultrasonography; PPV, positive predictive value; NPV, negative predictive value; P ⁄ IVH, peri- and intraventricular haemorrhage. Ultrasound Detection of White Matter Injury in Preterm Neonates Gerda van Wezel-Meijler et al. 31 calculated. Furthermore, to assess the influence of timing of CUS examinations on the predictive value of CUS, predictive values of PVEs, seen in a certain period (first, second, third, or fourth week after birth) were calculated. For statistical analysis, white matter on MRI was divided into two groups: normal and mildly abnormal versus moderately and severely abnormal white matter. The aspect of the lateral ventricles on CUS and MRI was also divided into two groups: normal versus abnormal shape and ⁄ or size of the lateral ventricles. Finally, the predictive values of individual CUS findings for unfavourable neurological outcome at 2 years corrected age, defined as either a developmental delay and ⁄ or CP, were calculated. RESULTS Patients A total of 130 very preterm infants were included in the study of whom 108 underwent MRI. In 67 of the 108 infants, MRI was performed before the postmenstrual age of 44 weeks. In the other 41 infants, MRI was postponed owing to their instable condition. As DEHSI is currently only described in children scanned around TEA, statistical analysis was confined to the 67 individuals with MRI around TEA. Table I shows the general characteristics and CUS findings of the whole study group and the subgroup of 67 infants scanned around TEA. Predictive value of CUS for MRI The predictive values of the CUS findings for the MRI white matter classification are listed in Table II. This table shows that presence of PVEs, regardless of characteristics (aspect, grade, and duration) is predictive of abnormal white matter on MRI. However, absence of PVEs does not predict normal white matter. In addition, presence of P ⁄ IVH is highly predictive of abnormal white matter on MRI, but again with a low NPV. Repeating our analysis for the 48 children without P ⁄ IVH, we found comparable predictive values of PVEs for abnormal white matter. Abnormal size and ⁄ or shape of the lateral ventricles, as seen around TEA, was also highly predictive of abnormal white matter, whereas normal size and shape of the ventricles did not predict normal white matter. We found no obvious improvement of predictive values, increasing the number of CUS examinations: if PVEs were seen in the first week, this predicted abnormal MRI in 73% of infants, with a sensitivity of 78%, specificity of 31%, and NPV of 42%. If PVEs were also seen in four consecutive weeks after the first week, the PPV remained at 73%, and the sensitivity and NPV increased slightly towards 87% and 50% respectively, but with a specificity decreasing to 25%. In addition, there was no influence of age at CUS examination on the predictive values of CUS: predictive values of PVEs seen in the first week were in the same range as those seen at a later age. Calculating predictive values of individual CUS findings for individual MRI findings, we found high PPV and sensitivity of PVEs for DEHSI, the NPV again being low. Inhomogeneous PVEs did not predict PWMLs, but the NPV was high (Table II). Follow-up Of the 67 infants who underwent MRI before the postmenstrual age of 44 weeks, follow-up was available for 50 (75%). Recommendations for neuro-imaging in very preterm neonates Serial CUS in 1st week No P/IVH P/IVH low frequency serial cUS for brain growth & maturation* serial cUS for complications P/IVH, brain growth & maturation* MRI around TEA *Intensify if complications occur. Abnormalities No abnormalities MRI around TEA No MRI Figure 3: Recommendations for neuroimaging in very preterm neonates. 32 Developmental Medicine & Child Neurology 2011, 53 (Suppl. 4): 29–34 A total of seven children (14%) had an unfavourable outcome at 2 years corrected age. Two children had a mental developmental index score ‡1 SD below the standard mean, six had a psychomotor developmental index score ‡1 SD below the standard mean, and four had CP. All the children with CP had a psychomotor delay and one also a mental delay. Predictive value of CUS for outcome P ⁄ IVH and abnormal size and ⁄ or shape of the ventricles were predictive of outcome at 2 years corrected age (PPV 34 and 31% respectively, negative predictive values 94%). The PPVs of the other CUS findings were 14 to 17%, with NPV 88 to 93%, indicating a high chance of a normal outcome when the CUS finding was absent. DISCUSSION White matter injury is probably responsible for most disabilities in very preterm neonates.14 As CUS is the most frequently used imaging modality for detecting brain injury in neonates at high-risk, its detection of white matter injury may be useful in targeting interventional therapy. This study assessed the predictive values of individual CUS findings for white matter injury on MRI and the influence of timing and frequency of CUS, aiming to optimize CUS protocols for detecting white matter injury. In addition, we assessed the predictive values of individual CUS findings for neurological outcome at 2 years corrected age. We found that presence of PVEs on CUS was predictive of abnormal white matter on MRI. However, absence of PVEs was not predictive of normal white matter. In other words, absence of changes in the white matter on CUS is no guarantee of a normal MRI. In addition, increasing the number of CUS examinations and varying the timing of CUS did not influence the reliability of CUS for detecting white matter injury. To our surprise, P ⁄ IVH was more predictive of abnormal white matter on MRI than PVEs. This may be for several reasons. First, P ⁄ IVH is reliably detected by CUS, therefore false-positive and false-negative diagnoses are rare.1 Second, P ⁄ IVH originates from and might damage the germinal matrix. This might have consequences for further development of glial-cell precursors and astrocytes, originating from the germinal matrix, possibly contributing to white matter injury.15 In addition, elevated free iron in cerebrospinal fluid resulting from intraventricular haemorrhage might catalyse radical formation and white matter injury may ensue. Furthermore, even mild ventricular dilatation may influence white matter development and P ⁄ IVH may cause microglial activation.16 We additionally found that presence of PVEs on CUS predicted DEHSI on MRI. In recent literature there is doubt whether DEHSI indeed presents white matter injury.17–19 We therefore feel it is not justified to conclude that PVEs are the CUS presentative of diffuse white matter injury. We found no association between inhomogeneous PVEs and PWMLs. This seems to be in conflict with results of an older study, in which a fair association between inhomogeneous PVEs on CUS and PWMLs on MRI was found. However, the latter study was retrospective, fewer infants were included, and the MRI was performed at variable ages, often during the preterm period.10 P ⁄ IVH and abnormal lateral ventricles were reasonably predictive of unfavourable outcome at 2 years corrected age, whereas all the other individual CUS findings did not predict unfavourable outcome. This is partly in agreement with another study, finding a higher incidence of neurological abnormality during the first year of life in very preterm infants with prolonged PVEs, P ⁄ IVH grade 2 or 3, and ventricular dilatation than in infants without these CUS abnormalities.20 Amess et al.21 assessed the predictive value of CUS for neurological outcome at 12 months corrected age and found high risk CUS findings to be predictive of abnormal neurological outcome (sensitivity 83%), but their high-risk CUS findings included more serious abnormalities than the individual CUS findings we assessed. Rademaker et al.22 found significant differences in motor and mental outcome at school age between very preterm infants with normal ⁄ mildly abnormal CUS findings and severely abnormal CUS findings. They included more infants and their follow-up period was much longer. De Vries et al.23 in a large prospective study among preterm infants, found major CUS abnormalities to be highly predictive of CP. Again, their major CUS abnormalities were more severe and differed from the individual CUS findings we assessed. Comparison of our study with the aforementioned studies is difficult, because of the changes in the character and definition of white matter injury over recent years. We found high negative predictive values of CUS for outcome around 2 years corrected age, indicating a high chance of a normal outcome when CUS abnormalities were absent. This is in accordance with the study by de Vries et al.23 showing high negative predictive values of absence of major CUS abnormalities for CP around 2 years of age. We acknowledge the limitations of this study. First, MRI could not be performed around TEA in all patients. We could therefore only analyse the data in a subgroup of our infants, implying a limited number of patients per white matter group and with individual CUS and MRI findings. Therefore the number of infants with some individual CUS findings, especially P ⁄ IVH grade 3 and PVEs grade 2, was too low to draw final conclusions about the prediction of these CUS findings for unfavourable outcome. Secondly, it is uncertain whether DEHSI represents white matter injury. Finally, our follow-up period is short. More subtle cognitive deficits, with possible consequences on school performance, may still develop. With respect to these limitations, we make the following conclusions: (1) If PVEs are present on CUS, regardless of timing, duration, and appearance, there is a significant chance of abnormal white matter on MRI. (2) If PVEs are seen any time during the neonatal period, additional CUS examinations do not increase the diagnostic performance of CUS for detecting white matter abnormality. Therefore, increasing the number of CUS examinations in these cases is of limited clinical importance. (3) P ⁄ IVH is highly predictive of abnormal white matter on MRI. (4) Absence of PVEs and P ⁄ IVH on CUS does not guarantee normal white matter on MRI. (5) P ⁄ IVH and ventricular dilatation, but not PVEs, seem to be reason- Ultrasound Detection of White Matter Injury in Preterm Neonates Gerda van Wezel-Meijler et al. 33 ably predictive of abnormal neurological outcome at 2 years corrected age. (6) Absence of any CUS abnormality in the white matter or lateral ventricles is highly predictive of a normal outcome at 2 years corrected age. The practical consequences of these conclusions are as follows (Fig. 3): (1) In very preterm neonates, CUS examinations in the first week of life are necessary to detect P ⁄ IVH. 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