Published online January 4, 2006
PEDIATRICS Vol. 117 No. 1 January 2006, pp. 1-8 (doi:10.1542/peds.2004-1719)
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Hemodynamics of the Cerebral Arteries of Infants With Periventricular Leukomalacia

Sumio Fukuda, MD, Takenori Kato, MD, Hiroki Kakita, MD, Yasumasa Yamada, MD, Mohamed Hamed Hussein, MD, Ineko Kato, MD, Satoshi Suzuki, MD and Hajime Togari, MD

Department of Pediatrics, Neonatology, and Congenital Disorders, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. This study investigated the developmental changes in blood flow in each cerebral artery among infants with and without periventricular leukomalacia (PVL), to elucidate the time of onset of PVL.

METHODS. Eight of 67 low birth weight infants were diagnosed through ultrasonography as having PVL with cyst formation. The mean cerebral blood flow velocities (CBFVs) in the anterior cerebral artery, middle cerebral arteries (MCAs), posterior cerebral arteries (PCAs), internal carotid arteries (ICAs), and basilar artery were measured with Doppler ultrasonography at postnatal days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, 56, and 70. Four of 8 infants with cyst formation and 1 of 59 infants without cyst formation developed cerebral palsy.

RESULTS. The mean CBFVs of infants with PVL were significantly lower in the anterior cerebral artery (days 14–70), the right MCA (days 14–70), the left MCA (days 14–70), the right PCA (days 7–70), the left PCA (days 5–70), the right ICA (days 7–70), the left ICA (days 7–70), and the basilar artery (days 14 and 28–70). The CBFVs in all arteries were also lower among those with PVL than among intact infants on day 0. The CBFVs increased postnatally in the PCAs of infants with intact brains, whereas they remained unchanged after day 14 or 21 among infants with PVL. There was a significant difference in the prevalence of cerebral palsy between the 2 groups.

CONCLUSIONS. We suggest that the total cerebral blood supply is decreased in cases of cystic PVL and that this reduction occurs just after birth, in a defined sequence, in the cerebral arteries. We conclude that the insult resulting in PVL might occur close to the time of birth.

Key Words: periventricular leukomalacia • cerebral blood flow velocity • cerebral ischemia • transcranial ultrasonography

Abbreviations: PVL—periventricular leukomalacia • CBFV—cerebral blood flow velocity • PCA—posterior cerebral artery • ACA—anterior cerebral artery • MCA—middle cerebral artery • BA—basilar artery • ICA—internal carotid artery • CP—cerebral palsy

Periventricular leukomalacia (PVL) is now considered the principal form of brain injury among preterm infants. PVL among very low birth weight infants is the major reason for their increased risk of developing a variety of neurologic sequelae; including motor dysfunction; delayed cognitive development; visual impairment; and epilepsy.1,2 The neurologic disabilities often result in cerebral palsy (CP), especially spastic diplegia.3 PVL has been defined as cyst formation with necrosis of myelinated fibers of the white matter around the trigone that is situated dorsal and lateral to the external angles of the lateral ventricles.4 Several studies investigated the correlation between diffuse-type PVL and mental retardation and other neurologic disabilities.5,6

Many authors have reported on the pathophysiologic features of PVL, with infection and ischemia now being considered to underlie its development. Chorioamnionitis is reported to be associated with PVL, and umbilical cord inflammation (as detected in placental samples) is one of the risk factors for PVL.7 Elevated interleukin-6 levels in umbilical cord blood sometimes are associated with subsequent PVL.8 These reports suggest that PVL occurs in the prenatal period. However, it is well recognized that insufficient blood flow in the watershed areas can induce white matter injury.9,10 Impairment of cerebrovascular autoregulation, especially among premature infants, is associated with the occurrence of PVL.11 This suggests that both prenatal and postnatal pathophysiologic mechanisms can induce PVL. One report suggested a correlation between fetal inflammation and reduced postnatal blood pressure as the cause of PVL.12 Therefore, in the present study we measured the cerebral blood flow velocities (CBFVs) in each of the cerebral arteries in relation to the time of onset of PVL.


   METHODS
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 METHODS
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The study group consisted of 67 low birth weight infants (birth weight: <2000 g) who were admitted to the NICU of Nagoya City University Hospital between June 2001 and June 2003. The gestational ages at birth ranged from 25 weeks to 34 weeks, and the birth weights ranged from 608 g to 1956 g. Diagnoses included jaundice, transient tachypnea of the newborn, pneumomediastinum, and respiratory distress. The criteria for inclusion in this study included the absence of lethal congenital anomalies and uncorrectable cardiac abnormalities. Parental informed consent (as approved by the ethics committee of the university) was obtained in all cases, before measurements were made. Patients were divided into 2 groups. Fifty-nine subjects were diagnosed as being without evidence of PVL (control group); 32 of those subjects underwent mechanical ventilation for 7 ± 9 days (mean ± SD), 26 subjects received inhalation oxygen therapy only, and 1 subject did not require oxygen therapy at any stage. A physician at our clinic determined whether infants were affected by CP by performing neurodevelopmental examinations, according to our standard protocol, at 12-month follow-up visits. Four or five visits were scheduled in the first 1 year of life. The neurologic examination results were considered normal if there were no muscle tone, reflex, or coordination abnormalities. Disability was diagnosed if the examination revealed abnormal postural reflexes associated with increased muscle tone, impaired motor function in at least the lower extremities, or spasticity. Such conditions would indicate spastic diplegia, hemiplegia, or quadriplegia. The remaining 8 subjects developed PVL with cyst formation, as detected with ultrasonography; 5 subjects underwent mechanical ventilation for 14 ± 12 days, and 3 subjects received inhalation oxygen therapy only. There were no cases of maternal illicit drug use or refractory patent ductus arteriosus that required ligation. Cystic PVL was diagnosed when cysts with diameters of >3 mm were detected with ultrasonography. Clinical perinatal infection is used to refer to cases of maternal fever or elevation of C-reactive protein levels in maternal blood.

Cranial ultrasonography was performed for each patient with a sonograph with a 5.0-MHz sector transducer (SSD-2200; Aloka, Tokyo, Japan). The transducer was placed first on the anterior fontanelle, and pulsations were observed in the anterior cerebral artery (ACA), in the bilateral internal carotid arteries (ICAs) alongside the sella turcica, and in the basilar artery (BA). In the transcranial plane, the transducer was placed in front of the ear, over the thin temporal window, to obtain a cross-sectional image of the brain and to allow the flow in the bilateral middle cerebral arteries (MCAs) to be measured. With a built-in analyzer, we determined the mean CBFVs on representative tracings. A Doppler instrument measured the CBFVs in the posterior cerebral arteries (PCAs) with the subject lying supine, with the head turned to the right or left side. Scans were obtained in all cases with the transducer placed on the posterior fontanelle for a horizontal view. Pulsations were obtained as a color flow image of both PCAs around the midbrain. The ambulatory segment of the PCA around (beside) the midbrain was sampled for measurements on both sides. The mean CBFVs were measured on postnatal days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, 56, and 70. PVL was diagnosed with cranial ultrasonography performed mainly at 21 or 28 days postnatally if a cyst of >3 mm was evident. Only 1 of the 8 infants with cyst formation showed a unilateral cyst. PVL was located in the white matter around the trigone in that study. One infant exhibited ventriculomegaly. The infants diagnosed as having PVL with ultrasonography showed thinness of the cerebral white matter and ventriculomegaly on later MRI scans. PVL was diagnosed with blinding with respect to the cerebral blood flow findings. None of the infants in the study exhibited any evidence of intracranial hemorrhage. Cranial ultrasound results were considered normal when no abnormalities or only mild echo densities were detected. Group differences for continuous data were examined with the Mann-Whitney U test and {chi}2 test, with statistical significance defined at P < .05.


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DISCUSSION
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Clinical data for the patients are listed in Table 1. The birth weight, gender ratio, gestational age, and Apgar scores at 1 and 5 minutes did not differ significantly between the control and PVL groups.


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  		TABLE 1 Clinical Data for Patients

 
The mean CBFV in the ACA were significantly lower for infants with PVL, compared with control infants, at days 14, 21, 28, 42, 56, and 70 (Table 2). The mean CBFV in the right MCA were significantly lower for infants with PVL, compared with control infants, at days 14, 21, 28, 42, 56, and 70 (Table 2). The mean CBFV in the left MCA were significantly lower for infants with PVL, compared with control infants, at days 14, 21, 28, 42, 56, and 70 (Table 2).


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  		TABLE 2 CBFV in Cerebral Arteries after Birth (Mean ± SD)

 
The mean CBFV in the right PCA were lower for infants with PVL, compared with control infants, at days 7, 10, 14, 21, 28, 42, 56, and 70. The mean CBFV in the right PCA for control infants increased with the number of postnatal days, but those for infants with PVL did not change after day 21 (Table 2). The mean CBFV in the left PCA were significantly lower for infants with PVL, compared with control infants, at days 5, 7, 10, 14, 21, 28, 42, 56, and 70. The mean CBFV in the left PCA for control infants increased with postnatal days, but those for infants with PVL did not change after day 21 (Table 2).

The mean CBFV in the right ICA were significantly lower for infants with PVL, compared with control infants, at days 7, 10, 14, 21, 28, 42, 56, and 70 (Table 2). The mean CBFV in the left ICA were significantly lower for infants with PVL, compared with control infants, at days 7, 10, 14, 21, 28, 42, 56, and 70 (Table 2). The mean CBFV in the BA were significantly lower for infants with PVL, compared with control infants, at days 14, 28, 42, 56, and 70 (Table 2).

Four of the 8 infants were diagnosed as having CP, 2 with quadriplegia and 2 with diplegia. One of the 59 infants developed quadriplegia later (Table 3).


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  		TABLE 3 Neurological Prognosis of Patients

 
The maximal and minimal blood pressure, heart rate, and PaCO2 values for infants are given in Table 4. The only significant difference between the 2 groups in these parameters from day 0 to day 70 was in the mean PaCO2 on day 5, which was significantly higher for infants with PVL, compared with control infants.


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  		TABLE 4 Maximal and Minimal Blood Pressure, Heart Rate and PaCO2 After the Birth

 
The date of patent ductus arteriosus closure for infants did not differ significantly between the 2 groups (Table 5). The incidence of premature rupture of the membrane also did not differ significantly between the 2 groups, whereas that of clinical perinatal infection did differ significantly (Table 6).


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  		TABLE 5 Date of Patent Ductus Arteriosus Closure For Patients

 

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  		TABLE 6 Premature Rupture of Membranes and Clinical Perinatal Infection Among Patients

 
The data on CBFVs in each of the cerebral arteries for patients with PVL, with and without perinatal infection, are given in Table 7. There were significant differences in the mean CBFVs in the right and left PCAs only on day 14; they were lower for infants with perinatal infection than for those without perinatal infection.


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  		TABLE 7 CBFVs in Cerebral Arteries in PVL Cases (mean ± SD)

 
The number of patients treated with the inotropes dopamine and dobutamine, drug dosages, and treatment durations are given in Table 8. There were no significant differences in the dosages between the 2 groups during the administration of the inotropes from day 0 to day 7. After day 7, no infant in either group received inotropes.


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  		TABLE 8 Cases and Levels of Inotropes (mean ± SD)

 

   DISCUSSION
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REFERENCES
 
PVL involves necrosis of the white matter and the dorsal and lateral external angles of the lateral ventricles.13 PVL has been defined as the presence of cysts on cranial ultrasound studies,14 but recent studies focused on the more detailed information obtainable with MRI.15,16 Volpe17 reported that PVL includes 2 types of lesions, ie, focal and diffuse. Usually diagnosis of cystic PVL is made in the neonatal period with ultrasonography, but diffuse-type PVL is not detectable in this way. This has led to numerous attempts to diagnose diffuse-type PVL with MRI, but more data are needed before this can be done reliably. It has been suggested that spastic diplegia is related to deep narrow cystic PVL lesions, whereas cognitive and behavioral deficits are related to diffuse wide lesions.17 It has also been reported that focal necrosis is complicated by the loss of all cellular elements deep in the periventricular white matter and that diffuse white matter involvement is characterized by injury to the glial cells.18 This may explain why PVL among premature infants is followed not only by white matter involvement but also by impaired cerebral cortical development. Therefore, we can assume that the total cerebral volume is lower for some premature infants with PVL than for premature infants without PVL. In this study, we found long-term reductions in the CBFVs in each of the cerebral arteries for infants with PVL. It was reported that mean CBFVs are correlated significantly with cerebral blood flow volumes.19 We therefore assumed that prenatal cerebral injury resulting in PVL led to the reduction in CBFVs in the present study. It is quite likely that some of our cases of cystic PVL were complicated by diffuse-type PVL in other regions of the white matter, which would indicate that diffuse-type PVL is a fine cystic PVL that cannot be detected with ultrasonography or MRI. Furthermore, we assume that cystic- and diffuse-type PVL sometimes exist simultaneously in an infant. Cases of PVL with cyst formation manifest as severe large lesions in the cerebral white matter parenchyma. The pathophysiologic features of cerebral injury seem to vary among patients, and there are some infants with cystic lesions who do not develop CP. Several studies have shown that approximately one half of infants with CP have lesions that are detectable with neonatal ultrasonography.20,21 By using sequential, high-resolution, cranial ultrasonography with a 7.5-MHz transducer, De Vris et al22 found that 79% of CP cases had ultrasonographic abnormalities of cystic PVL. There is a possibility that diffuse cerebral injury, and not cystic lesions, is the main cause of the sequelae of so-called PVL. It is thus likely that some infants diagnosed as having cyst formation with cranial ultrasonography and MRI will develop normally. Therefore, the hemodynamic features in cases complicated by only diffuse-type PVL require additional investigation.

The energy requirements of the fetal and early newborn brain are low.23 In particular, the premature newborn brain exhibits low cerebral oxygen consumption as a result of nonoxidative glucose metabolism.24,25 Therefore, the metabolism of cerebral tissue increases gradually after early suppression during the first few postnatal days.23 The gradual increase in CBFVs among normal infants reflects the rising metabolic demand of the growing brain during the neonatal period.26,27 Three-dimensional MRI and tissue segmentation of the human infant brain have revealed that the total brain tissue volume increases linearly from 29 to 41 weeks after conception.28 After the neonatal period, the total cerebral blood flow volume increases from childhood to adulthood.29 The injured white matter might have a lower blood flow requirement, and it is therefore suggested that the brain parenchyma in which PVL developed received an insufficient blood volume, compared with normal infants. It has been reported that the volumes of cerebral cortical gray matter and total brain myelinated white matter at term are lower among premature infants with PVL than among premature infants without PVL and normal term infants.30 MRI has revealed that not only the entire corpus callosum but also all brain regions except the vermis are significantly smaller among patients with PVL.31,32 The results from the present study suggest that the impairments extend to all cerebral tissue during or just before delivery.

The pathogenesis of neonatal brain damage seems to be multifactorial.33 There are many reports on the timing of injury in the perinatal period that results in PVL, but the exact timing of the brain injury remains controversial.34 Yanowitz et al35 showed that histologic evidence of chorioamnionitis was associated with elevated concentrations of interleukins 6 and 1 in umbilical cord blood, increased newborn heart rate, and decreased blood pressure. Histologic chorioamnionitis is a strong predictor of an adverse neonatal neurologic outcome, particularly PVL.36 Concentrations of cytokines and interleukins are increased in both neonatal blood and amniotic fluid in both CP and PVL.37 These studies suggest that the cause of PVL, intrauterine infection, occurs before delivery, and our results are consistent with this. However, the present study also suggests that there is another cause of PVL in addition to infection, namely, cerebral ischemia and hypoxia among those affected by neonatal asphyxia, as evidenced by low Apgar scores at 1 minute for patients with PVL. Ischemia and hypoxia might be attributable to the loss of autoregulation of neonatal cerebral hemodynamics,38,39 ie, there might be a correlation between a prenatal insult to autoregulation and the cause of PVL. In the present study, the CBFVs in each of the arteries were lower (although not significantly) on day 0 among patients with PVL than among control infants, and the reduction recovered after day 1. This suggests the presence of an insult to the autoregulation of cerebral blood flow and systemic hemodynamics before delivery, resulting from infection or asphyxia, recovery from which before delivery leads to normal cerebral hemodynamics from day 1 or 2. However, cerebral blood flow as high as that for intact infants becomes unnecessary for the parenchymal injury among infants with PVL from day 14; therefore, the CBFVs do not increase like those of control patients thereafter.

However, chronic ischemia starting from postnatal day 1 and intermittent occlusion of the umbilical cord in sheep both have been shown to result in the development of PVL.33,40 Analyses of electroencephalographic findings within 72 hours after birth suggested that the injury occurs just before birth among infants who develop PVL.41,42 Hypocarbia is also involved in the cause of PVL.43 Therefore, many factors that act before, during, and after delivery can produce PVL,44 but the present data suggest that PVL is induced in the prepartum period and/or during labor.


   FOOTNOTES
 
Accepted Apr 8, 2005.

Address correspondence to Sumio Fukuda, MD, Department of Pediatrics, Neonatology, and Congenital Disorders, Nagoya City University, Graduate School of Medical Sciences, Kawasumi, Mizuho-ku, Nagoya, Aichi 467-8601, Japan. E-mail: fukuda{at}med.nagoya-cu.ac.jp

The authors have indicated they have no financial relationships relevant to this article to disclose.


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