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a Fetal/Neonatal Neurology Research Group, Department of Neurology
c Clinical Research Program, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts
b Radiology
d Newborn Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
e Department of Newborn Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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METHODS. We retrospectively evaluated all cranial ultrasounds and medical records of 58 premature infants with periventricular hemorrhagic infarction. We assigned each subject a severity score based on extent of echodensity, unilateral versus bilateral, and presence or absence of midline shift. A neurologic examination was performed after 12 months adjusted age.
RESULTS. The parenchymal echodensity of periventricular hemorrhagic infarction most often involved parietal and frontal territories and evolved into single and/or multiple cysts. One quarter of cases were bilateral, and nearly 70% were extensive. Higher severity scores were significantly associated with pulmonary hemorrhage and low bicarbonate levels and with outcomes of fatality, early neonatal seizures, and motor disability.
CONCLUSIONS. Despite advances in perinatal medicine, periventricular hemorrhagic infarction remains an important complication of prematurity. Periventricular hemorrhagic infarction can be graded using a scoring system based on sonographic characteristics. Higher severity scores predict worse outcome. Such severity scoring could improve the clinician's ability to counsel parents regarding management decisions and early intervention strategies.
Key Words: ultrasonography • periventricular hemorrhagic infarction • grade IV intraventricular hemorrhage • premature infants
Abbreviations: PVHI—periventricular hemorrhagic infarction • GM-IVH—germinal matrix–intraventricular hemorrhage • CUS—cranial ultrasonography • PVL—periventricular leukomalacia
Periventricular hemorrhagic infarction (PVHI) is an acquired brain lesion with major impact on the neurodevelopmental outcome of infants who survive premature birth. PVHI has been considered to be the most severe (grade IV) form of germinal matrix–intraventricular hemorrhage (GM-IVH). A number of reports1–6 have suggested, however, that rather than representing simple parenchymal extension of the intraventricular blood, PVHI is a complication of GM-IVH, which results from hemorrhagic transformation of a venous infarction. For many years, neonatal cranial ultrasonography (CUS) has been the key diagnostic tool for GM-IVH and PVHI in premature infants. Detailed structural and timing characteristics of PVHI by CUS initially were described 
25 years ago.7 Over the course of the next 2 decades, additional studies delineated a range of sonographic characteristics of PVHI.8–16 Although specific CUS diagnostic criteria for PVHI have been proposed,1, 13, 17, 18 comparison of the CUS features between various studies is limited because of the lack of a consistently used CUS scoring system for PVHI.
We therefore set out to examine the extensive CUS database at our center to describe the ultrasonographic features of PVHI in recent years. Our goals were (1) to define the extent and the topography of PVHI in the current era, (2) to delineate the typical findings on CUS with evolution of PVHI, (3) to develop a CUS-based scoring system to describe the structural severity of PVHI during the early newborn period, and (4) to determine the relationship between such a sonographic severity score and perinatal risk factors and outcome.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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CUS Protocol
During the 6-year study period, CUS studies at our center were performed using the Acuson Sequoia instrument (Siemens, Mountain View, CA) equipped with a 6.5- to 8.5-MHz probe. Standardized images that were acquired for every CUS study included anterior fontanel views (6 angled coronal views, 2 midsagittal views, and 3 parasagittal views on each side), posterior fontanel views (2 parasagittal views of the occipital horns of the lateral ventricles), and posterior fossa views (angled transaxial images of the midbrain and cerebellum acquired through the mastoid [3 views] and sphenoid [2 views]) regions. Between 1997 and 1998, posterior fossa imaging was not performed routinely. The clinical CUS protocol in our NICU remained consistent during the study period, calling for a minimum of 2 CUS examinations to be performed during the first week of life and an additional CUS at 30 days of age. Additional studies were performed when clinically indicated.
CUS Classification of Lesions
Neonatal CUS scans of all study infants were evaluated by 2 of the authors (C.B.B. and H.B.), who were blinded to the infants' clinical course and outcome. In 5 cases of disparity between these 2 reviewers, a third reviewer (A.J.d.P.) was used as a tie-breaker. The time (date and hour) of each CUS study was recorded. We used the following CUS diagnostic criteria:
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5 mm in diameter on the parasagittal view. In all cases, the extent of the lesion on parasagittal view was confirmed on corresponding angled coronal views. On the basis of the number of territories involved, we categorized the extent of injury as localized (ie, limited to 1 territory) or extensive (ie, involving 2 territories). We assessed the mass effect of the PVHI lesion on the basis of the presence or absence of midline shift on coronal image (Fig 1b). We documented the timing of the first appearance of GM-IVH and PVHI, the temporal evolution to maximal size of PVHI, and the time of first appearance of cystic changes. We also evaluated by visual inspection the sonographic evolution for the presence of single large cyst, multiple small cysts (
5 mm), and ventriculomegaly.
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2 territories [based on the worse side if bilateral]). A CUS study that showed PVHI with none of these features received a score of 0, whereas a study that showed all 3 features received a score of 3.
Clinical Data Collection and Neurologic Examination
We reviewed the hospital charts of all study infants for pertinent demographic (gender, birth weight, and gestational age at birth) and clinical information, including intrapartum history, blood gas data, and postnatal information. We defined abnormal fetal heart rate as sustained fetal bradycardia <100 beats/minute, loss of variability, and/or late decelerations. Pressor support was defined as use of inotropic agents within the first 5 days of life. Patent ductus arteriosus was counted when diagnosed by echocardiogram before day of life 5 or when diagnosed clinically before day of life 5 and confirmed by subsequent echocardiogram. For all patients, we documented neonatal survival, whether life support was withdrawn, early (<5 days of age) or later neonatal seizures, and the requirement for a ventriculoperitoneal shunt.
A pediatric neurologist (H.B. or A.J.d.P.) examined all survivors at or above 12 months' adjusted age for prematurity using a predefined, formal neurologic examination that included assessment of motor function (deep tendon reflexes, muscle tone, muscle strength, coordination, and gait), cranial nerves, and special senses. Neuromotor findings were categorized as normal or abnormal. Abnormal neuromotor examination was defined as any abnormality in tone, posture, or strength. Abnormalities then were subclassified according to type (hemiplegia, diplegia, quadriplegia, and dystonia). Cranial size (>12 months' adjusted age) was considered abnormal when measured below the 2nd or above the 98th percentile. Age on follow-up examination was adjusted for prematurity for infants who were younger than 24 months' chronological age.
Statistical Analysis
We categorized our data according to birth weight groups (<750, 750–1500, and 1500–2500 g). We additionally categorized the PVHI scores into low scores (0–1) and high scores (2–3). Simple comparisons between fatal and nonfatal PVHI and between low or high PVHI scores were made for continuous variables by Student's 2-tail t test and for dichotomous variables by the Fisher's exact test. Multiple logistic regression was used on the strongest risk factors detected by the univariant analysis. Comparisons among the 4 ordered score categories (0–3) and all outcome factors were made by the exact Cochrane-Armitage trend test and by logistic-regression analysis. SAS (SAS Institute, Cary, NC) and SPSS (SPSS, Inc, Chicago, IL) were used for all computations.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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CUS Findings
The first, second, and third CUS studies in the study infants were performed at mean (±SD) postnatal ages of 1.3 days (±1.2), 3.6 days (±2.3), and 5.9 days (±2.6), respectively. By the seventh day of life, infants with PVHI had a median of 2 (range: 1–4) CUS studies performed. Throughout their NICU stay, study neonates had a median total of 10 (range: 1–54) CUS studies performed.
The sonographic findings in our 58 neonates with PVHI are presented in Table 1. PVHI was more often unilateral than bilateral (43 vs 15 cases). The unilateral lesions occurred equally often on the right and the left (20 vs 23 respectively; P = .66). In the bilateral cases, PVHI was more often extensive (93%; 14 of 15), involving 2 territories, as compared with cases of unilateral PVHI, for which 58% (25 of 43) were extensive (P = .01). The extensiveness of PVHI was similar for the following birth weight categories: <750 g, 21 (68%) of 31; 750 to 1500 g, 16 (70%) of 23; and 1500 to 2500 g 2 (50%) of 4 (P = not significant). In addition, no significant association was found between gestational age at birth and the extensiveness of PVHI (P = not significant). The topographic distribution of PVHI in our patients is presented in Fig 2; the parietal territory was most commonly involved, followed by the frontal, occipital, and temporal territories.
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Forty-seven patients who received a diagnosis of PVHI within the first 4 days of life had a median of 2 CUS scans (range: 1–3) during this early period. Among these 47 patients, the median age at CUS diagnosis of PVHI was 46 hours (range: 4–96 hours) from time of birth. PVHI was diagnosed either concurrently with GM-IVH (n = 41, 87%) or after the diagnosis of GM-IVH (13% [n = 6]). In these 47 cases, the PVHI lesion size increased on sequential CUS studies in 22 (47%; mean ± SD lag time: 54 ± 38 hours), whereas in the remaining 25 (53%) cases the size of the PVHI was at its maximum at the time of the first diagnosis on CUS. In no case did the GM-IVH appear after the PVHI.
Among the 35 infants who survived the neonatal period, the echodense PVHI lesion most often evolved into 1 of 3 distinct CUS patterns: a single large cyst (66% [n = 23]), multiple small cysts (9% [n = 3]), or a combination of large and small cysts (23% [n = 8]). In 1 infant, follow-up CUS images were not available. Median time until the first appearance of cystic changes was 7 days (range: 1–15 days) after the initial diagnosis of PVHI.
Thirty-four (97%) of the 35 surviving infants developed ventriculomegaly after day of life 7. By the time of discharge, ventriculomegaly was present in 80% (n = 28) of surviving infants, with 27 (77%) having asymmetric and only 1 (3%) having symmetric ventricular dilatation. Three of the surviving infants (9%; mean ± SD gestational age: 27.2 ± 0.2 weeks; birth weight: 1065 ± 332 g) developed CUS findings of concomitant contralateral PVL.
Clinical Course and Outcome of PVHI
Eleven (19%) infants experienced clinical seizures during their NICU stay (5 of them before day of life 5), and 13 infants required ventriculoperitoneal shunts. The mortality rate in our infants with PVHI was 40% (n = 23). Twenty-two of 23 deaths followed a decision to withdraw life support, thus limiting our ability to associate some clinical factors and neonatal death. Nevertheless, fatal cases had a significantly lower mean (± SD) gestational age (25 ± 2 weeks) and birth weight (705 ± 162 g) than survivors (27 ± 2 weeks and 962 ± 396 g; P < .004), as well as an earlier PVHI diagnosis than survivors (45 ± 32 vs 69 ± 44 hours; P = .03). Finally, among the 45 infants who had a posterior fossa view by CUS, the presence of blood in the fourth ventricle was significantly more common in those who died (14 [93%] of 15 vs 17 [56%] of 30; P = .016). Of the 35 survivors, 31 (89%) underwent long-term follow-up neurologic examinations after 12 months' adjusted age. These were performed at a mean ± SD adjusted age of 36.7 ± 20 months. Of these 31 infants, 12 (39%) had a normal neurologic examination. Neuromotor abnormalities were found in 19, including 11 (35%) with spastic hemiplegia, 4 (13%) with spastic diplegia and hemiplegia, and 4 (13%) with spastic quadriplegia (of these, 2 also exhibited dystonia). Also among these 31 survivors, abnormal head circumference was documented in 10 cases (32% [6 microcephalic and 4 macrocephalic]).
Relationship of PVHI Severity Score to Perinatal Factors and Outcome
Univariate analysis of risk factors revealed that high PVHI scores were associated with low bicarbonate levels during the first 2 days of life and with pulmonary hemorrhage (P < .02; Table 2). Multiple logistic regression of 3 predictors (pulmonary hemorrhage, low Apgar score at 5 minutes, and low bicarbonate) showed that pulmonary hemorrhage is an independent predictor for higher PVHI severity scores (P = .014), whereas low Apgar score at 5 minutes was borderline significant (P = .049) and low bicarbonate was not statistically significant (P = .11).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Structural Characteristics of PVHI by CUS
Our findings show that the appearance of PVHI by CUS in our NICU is severe in the majority of infants: two thirds had extensive distribution, one quarter were bilateral, and almost half had midline shift. In addition, we found a predilection of PVHI for the parietal and frontal territories. Our observations corroborate previous reports8–11, 20, 23 and confirm that in the current era, PVHI remains a serious and important complication of premature infants. Unlike previous studies,8, 20 there was no left-sided predominance of PVHI in our study, the incidence of right- and left-sided lesions being equal.
Timing of CUS Diagnosis of PVHI
Our results show that in most infants, PVHI is diagnosed in the first 4 days of life. Even in our late cases (diagnosed after day of life 4), an earlier presentation may have been masked by low scanning frequency, presumably as a result of the milder clinical presentation of these infants. It is interesting that a diagnosis of PVHI on the first day of life, as seen in one fifth of our infants, raises the possibility of an intrapartum or antepartum onset for these cases. The early neonatal presentation of PVHI in our study, also previously recognized,10, 14 underscores how critical the first days of life (including the antenatal or intrapartum period in some cases) are for the development and the prevention of this severe lesion.
Evolution of PVHI by CUS
Our data suggest that the parenchymal echodensity of PVHI may evolve in 3 broad ways. The most common end result is a single large cyst, with or without communication with the lateral ventricles. The second most common pattern is that of multiple small cysts combined with a large cyst, a combination previously described in infants with PVHI.8, 9, 11, 12, 24 Third and least common, PVHI results in multiple small cysts.
The presence of multiple small cysts in 9% of our survivors with PVHI is a morphology that is seen more commonly in the arterial end zone lesion of PVL. Possible mechanisms for these multicystic evolutions are as follows. First, they may represent a transitional phase of the venous infarct toward confluence into a single, larger cyst. Conversely, they may represent arterial ischemic lesions that occur in combination with the larger venous infarct.
In our study, a high proportion of involved infants developed ventriculomegaly, which may have been attributable to periventricular tissue loss, impaired cerebrospinal fluid dynamics with increased ventricular pressure, or both. A recent study25 also found ventricular dilatation in >70% of survivors with PVHI. Concomitant contralateral cystic PVL was found in 9% of our patients. Our data probably underestimate the frequency of associated PVL given the lack of CUS sensitivity for diagnosis of the diffuse form of PVL.26
Associations of Ultrasonographic Features With Risk Factors and Outcome
We developed a CUS-based PVHI severity scoring system and correlated it with the presence of clinical risk factors and outcomes. Previous studies27–29 have suggested that birth weight, gestational age, and hemodynamic disturbances are important antecedents of PVHI. Our data do not support an association between these known risk factors and PVHI severity. Our multivariate modeling suggests that pulmonary hemorrhage is an independent predictor of PVHI severity. Potential mechanisms to explain this association include intrinsic coagulation disturbance and consumption of clotting factors. It also has been suggested that hemorrhage into the lung and brain could occur during reperfusion of vulnerable areas that previously were affected by ischemia.10
To examine the validity and the predictive ability of our PVHI severity scoring system, we tested our score against short- and long-term outcome factors. We found a strikingly significant relationship between PVHI score and the likelihood to withdraw care, the development of early neonatal seizures, and abnormal neuromotor examination beyond 12 months' adjusted age. The grouping of 3 structural sonographic severity items into a single scoring system therefore may allow improved severity assessment and prognostication of PVHI as opposed to relying on separate factors.
In contrast to a previous study that associated poor neuromotor outcome with posterior PVHI,11 we found that anterior frontal involvement was associated with abnormal neuromotor examination. We did not find a significant relationship between fatality and topography of PVHI. It is interesting that posterior lesions were associated with smaller head size in survivors of PVHI; however, the mechanism of this association is unclear.
As a retrospective analysis, our study has several potential limitations. Although our data provide some insights into the timing of PVHI diagnosis by CUS, our reliance on a routine clinical CUS protocol with a limited number of studies precludes the precise timing of PVHI onset. We also cannot retrospectively assign causality to the risk factors that are associated with the complex PVHI severity scores that were assigned via our system. Finally, the potential of our PVHI severity scoring to predict long-term cognitive outcome is not addressed by this study and should be evaluated further.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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ACKNOWLEDGMENTS |
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We thank Shaye Moore for assistance with manuscript preparation and Amy Kroeplin and Gene Walter for data management.
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FOOTNOTES |
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Address correspondence to Adré J. du Plessis, MD, Department of Neurology, Fegan 11, Children's Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail: adre.duplessis{at}childrens.harvard.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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