PEDIATRICS Vol. 104 No. 5 November 1999, pp. 1077-1081

Determination of Timing of Brain Injury in Preterm Infants With Periventricular Leukomalacia With Serial Neonatal Electroencephalography

Fumio Hayakawa, MD^*, Akihisa Okumura, MD, Toru Kato, MD^§, Kuniyoshi Kuno, MD^§, and Kazuyoshi Watanabe, MD

From the ^* Department of Pediatrics, Okazaki City Hospital, Okazaki;  Nagoya University School of Medicine, Nagoya; and ^§ Anjo Kosei Hospital, Anjo, Aichi, Japan.

	ABSTRACT

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Objective.  The aim of this study was to determine the timing of brain injury in infants with periventricular leukomalacia (PVL) with serial electroencephalography (EEG) recordings during the neonatal period.

Patients and Methods.   We evaluated 172 preterm infants having a gestational age <33 weeks and weighing <2000 g. Initial EEG was recorded within 72 hours of life and then recorded once every 1 to 4 weeks. Serial cranial ultrasonography was performed and cystic PVL was diagnosed when multiple cystic formations of >3 mm in diameter were observed.

Results.  Of the172 infants studied, 26 were diagnosed as having cystic PVL by ultrasonography. EEG abnormalities were observed in 25 of 26 infants with PVL, although EEG abnormalities were seen in 20 of 146 infants without PVL. The initial EEG recordings were normal in 7 infants, but EEG abnormalities were observed later in 6 of these infants. In these 6 infants, the timing of injury was presumed to be postpartum. Only acute stage abnormalities were observed on initial EEG recording in 14 infants, and the timing of injury was presumed to be just before or around birth. Chronic stage abnormalities were recognized already on initial EEG recordings in the other 5 infants, and the timing of injury was presumed to be some time before birth.

Conclusions.  Our study indicates that it may be possible to determine the timing of injury in infants with PVL by serial EEG recordings.  Key words:  neonatal electroencephalography, periventricular leukomalacia, timing of injury, ultrasonography.

Periventricular leukomalacia (PVL) is a very important predictor of cerebral palsy (CP) in preterm infants.^1,2 Some infants with PVL can be diagnosed by ultrasonography during the early neonatal period. Many risk factors have been reported previously,^3-6 but infants who later develop PVL often may have multiple risk factors. For this reason, it is impossible to decide the cause of PVL or the time that brain insult occurred to each patient, although PVL is known to be an arterial border zone infarct caused by an ischemic insult.^7-9

Although ultrasonography is useful to the diagnosis of PVL, ~2 or 3 weeks are required from brain insult to cyst formation on ultrasonography.^10,11 Therefore, it is not easy to decide timing of brain injury from ultrasonographic findings. Electroencephalography (EEG) is known to be a sensitive means to evaluate brain function in preterm infants.^12,13 Because EEG is not invasive, we can record it repeatedly for an infant. Our previous reports on EEG recordings in preterm infants reveal that different patterns of EEG abnormalities are recognized:¹⁴ acute stage EEG abnormalities reflect suppression of EEG activities caused by acute brain insult, and chronic stage EEG abnormalities reflect brain dysfunction caused by irreversible brain lesion.

The aim of this study is to determine the timing of brain injury in infants with PVL with serial EEG recordings during the neonatal period.

	SUBJECTS AND METHODS

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We evaluated preterm infants, having a gestational age <33 weeks and weighing <2000 g, who were admitted to Anjo Kosei Hospital from 1989 to 1993. During this period, 230 infants were admitted. Infants who died in the early neonatal period or had chromosomal abnormalities and/or multiple congenital anomalies were excluded from the study. Infants who had grade 4 periventricular parenchymal hemorrhage that was distinguishable from PVL based on ultrasonographic findings¹⁵ also were excluded, because developmental outcome could be affected by periventricular parenchymal hemorrhage. Eventually, 172 infants completed the study, including ultrasonography, EEG, and follow-up. The gestational age and birth weight of these infants were 24 to 32 weeks (average: 29.4 weeks) and 566 to 1998 g (average: 1359 g), respectively.

Cranial Ultrasonography

Cranial ultrasonography was performed at least twice within the first week of life, and thereafter, one to three times per week, using 5-MHz or 7.5-MHz sector SONOS 2000 (Hewlett-Packard, Palo Alto, CA). Coronal and sagittal sections from anterior fontanelle were examined. Cystic PVL was diagnosed when multiple cysts >3 mm in diameter were observed.

EEG

EEG was recorded using bipolar conduction with eight surface electrodes (AF3, AF4, C3, C4, O1, O2, T3, and T4), according to the (10-20) international methods as previously reported.¹⁶ The EEG was recorded for >30 minutes during the period from being awake until falling asleep spontaneously. Time constant was 0.3 second, and paper speed was 3 cm per second. The initial EEG was recorded within 72 hours of life and then recorded once every 1 to 4 weeks. When some clinical event occurred, additional EEG recordings were performed. All EEG recordings were evaluated by 3 well trained neonatal neurologists (F.H., A.O., and T.K.). EEG results were judged to be abnormal when all 3 analysts agreed.

Two kinds of EEG abnormalities were evaluated, according to the criteria that we proposed previously.¹⁷ When brain insult has occurred, EEG activity shows varying degrees of acute stage EEG abnormalities. The EEG activity gradually recovers when an insult disappears and is replaced by chronic stage EEG abnormalities if the brain damage is severe enough. Acute stage EEG abnormalities were diagnosed as present when at least one of the following abnormal findings was observed. Decreased continuity was recognized primarily as prolonged interburst interval during discontinuous tracing. Voltage suppression was recognized as low voltage  activities throughout the EEG recording. Attenuated, faster activities were recognized by a decreased quantity of -, -, and -waves. Chronic stage EEG abnormalities were characterized by changes in wave forms without signs of acute depression. Chronic stage EEG abnormalities were judged positive when a disorganized pattern was recognized.¹⁴ Abnormal sharp waves, such as positive rolandic sharp waves, were associated often, but not always, with disorganized patterns. Even if paroxysmal abnormalities were present, background EEG was evaluated according to the criteria described above.

Follow-up

Psychomotor development was examined every 3 months after discharge at least until 18 months of corrected age. We paid close attention to spasticity of the lower extremities, such as tight popliteal angle, foot joint tightness, and hyperreflexia in the deep tendon reflex. Spastic diplegia was diagnosed when an infant, who displayed spastic gait or could not walk, had signs of spasticity of the lower extremities. Cranial magnetic resonance imaging was performed during late infancy to early childhood, if an infants had psychomotor retardation or spasticity.

Statistical Analysis

Statistical analysis between the two groups was performed using unpaired t tests and ² tests. Statistical significance was accepted at the level of P < .05.

	RESULTS

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Of the 172 infants studied, 26 were diagnosed as having cystic PVL by ultrasonography. Clinical characteristics of infants with and without PVL are shown in Table 1. Gestational age did not differ significantly between infants with and without cystic PVL. Birth weight was significantly lighter in infants with PVL than in those without PVL. EEG abnormalities were observed in 25 (96%) of 26 infants with PVL at some time during the neonatal period. Twenty-one (91%) of 23 infants who survived with PVL later developed spastic diplegia. In contrast, EEG abnormalities were seen in 20 (14%) of 146 infants without PVL, and 13 (9%) of 141 survivors developed spastic diplegia. The percentages of EEG abnormalities and spastic diplegia were significantly higher in infants with PVL than in those without PVL.

The relationship between EEG abnormalities and later CP is shown in Table 2. Of the 18 infants with both acute and chronic stage abnormalities, 16 (89%) developed CP, whereas only 5 (4%) of 123 infants with normal EEG results did. CP was recognized in 7 (50%) of 14 infants with only acute stage abnormalities and 6 (67%) of 9 infants with only chronic stage abnormalities.

Initial EEG Findings in Infants With PVL

Initial EEG results were normal in 7 infants. In 14 infants, only acute stage abnormalities were observed on initial EEG recordings. In the other 5 infants, chronic stage abnormalities were already recognized on initial EEG recordings.

Infants With Normal Initial EEG Results (Fig 1)

In 6 of 7 infants, EEG abnormalities were observed some time after 72 hours of life. Acute stage EEG abnormalities were seen in 5 of these infants (cases 1, 2, 4, 5, and 6) and were followed by chronic stage EEG abnormalities. In another infant (case 3), chronic stage EEG abnormalities were observed without antecedent acute stage EEG abnormalities. The timing of injury was presumed to be postpartum in these 6 infants. Chronic stage EEG abnormalities preceded cystic degeneration on ultrasonography in 5 infants. No EEG abnormalities were recognized in 1 infant (case 7), and the timing of the injury was undetermined. Gestation was the shortest and birth weight was the lowest in infants with presumed postpartum injury. The date of cystic degeneration on ultrasonography was the most delayed in this group (Table 3).

View larger version (33K): [in this window] [in a new window]   Fig. 1.   Chronological EEG change in infants with normal initial EEG.

Infants With Acute Stage Abnormalities Only on Initial EEG Records (Fig 2)

The timing of injury was presumed to be just before or around birth in these infants, based on our hypothesis of chronological EEG change. In 11 of 14 infants, chronic stage EEG abnormalities appeared after acute stage abnormalities.

View larger version (40K): [in this window] [in a new window]   Fig. 2.   Chronological EEG change in infants with acute stage abnormalities only within 72 hours of life.

Infants With Chronic Stage Abnormalities on Initial EEG Records (Fig 3)

The timing of injury was presumed to be some time before birth in these infants, because initial EEG already displayed chronic stage abnormalities and the average date of cystic degeneration on ultrasonography was 4 days earlier than those with acute stage abnormalities only (Table 3). Acute stage EEG abnormalities were associated with chronic stage EEG abnormalities in 3 infants on initial EEG readings, whereas chronic stage abnormalities alone were seen in 2 infants. Gestation was the longest and birth weight was the heaviest in this group (Table 3).

View larger version (30K): [in this window] [in a new window]   Fig. 3.   Chronological EEG change in infants with chronic stage abnormalities within 72 hours of life.

	DISCUSSION

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PVL is well-known to be an important predictor of CP in preterm infants.^1,2 Many reports on risk factors of PVL have been published.^3-6 Determining the timing of the injury, using ultrasonography or pathologic methods, is not easy. Unless cystic change was observed during the antenatal or the very early neonatal period, one cannot determine antenatal injury clearly. Cystic change on ultrasonography often appears at ~3 weeks of life. Therefore, the studies on risk factors tend to focus on postnatal events, and antenatal fetal condition is not investigated fully. In our hospital, EEGs from the early neonatal period have been performed routinely for >10 years. We noticed that there is a relationship between chronological EEG change and neurological outcome. Our previous study of EEG readings in preterm infants elucidated the fact that the disappearance of acute stage abnormalities and the appearance of chronic stage abnormalities were recognized about 1 week after acute stage abnormalities were first observed.¹⁴ Therefore, we believe that serial EEG recordings may be able to help us to determine the timing of injury in infants with PVL. Continuous EEG recording also is considered useful in the diagnosis, not only of the presence, but also of the timing, of brain injury.¹² Continuous EEG recording might be superior to serial intermittent EEG recording for detecting subtle postpartum injury. However, continuous EEG recordings are sometimes difficult to perform, because preterm infants are prone to unstable and ill conditions.

From the results of serial EEG recordings, the timing of injury can be judged postpartum, if EEG results were normal during the early neonatal period but afterward acute stage EEG abnormalities appeared, followed by chronic stage abnormalities appeared; just before or around birth, if EEG results revealed acute stage abnormalities only during the early neonatal period; and sometime before birth, if EEG results revealed chronic stage abnormalities during the early neonatal period. One limitation of this study is that the first EEG was recorded within 72 hours of life, not immediately after birth. Although the first EEG should be obtained as early as possible, EEG recordings immediately after birth are often not practical because preterm infants usually need to be stabilized by intensive care. We acknowledge that it is difficult to distinguish perfectly between a brain injury that occurred several hours after birth from one that occurred just before birth. We mean that around birth can include the first few hours after birth.

From the results of our study, PVL caused by definite postpartum injury was observed in only 6 (23%) of 26 infants with PVL. In contrast, EEG already demonstrated abnormalities in the early neonatal period in the majority of the infants with PVL. Brain injury was considered to occur within a few days before birth, because cystic degeneration occurred 4 days earlier in infants whose timing of injury was presumed to be some time before birth than in those whose timing of injury was presumed just before or around birth. These results indicate that some adverse event occurred before birth and caused brain injury, resulting in depression of EEG activities. General condition was rather stable during the early neonatal period in most infants whose timing of injury was presumed to be some time/just before or around birth. Discrepancy between clinical conditions and EEG findings was characteristic of preterm infants. This makes it difficult to notice that an infant already suffered from brain injury.

Because a considerable number of infants who were born during the study period unfortunately were lost to follow-up, the percentage of infants with CP as high. EEG readings and ultrasonographic findings were normal in most of the infants who were lost to follow-up. Eventually, the percentage of infants with EEG abnormalities and/or ultrasonographic abnormalities became higher than was expected. However, we believe that the value of our study is not lessened, because the percentage of CP was extremely low among infants with normal EEG and ultrasonography.

Our study demonstrated the usefulness of serial EEG recordings in the determination of the timing of injury in infants with cystic PVL. However, there are some limitations in the application of our methods to infants with non-cystic PVL. We clearly identified some infants with periventricular hyperechodensities without cystic changes. The neurologic sequelae in these cases are usually mild, if they are present. EEG abnormalities are also mild and are not always easy to detect. For these reasons, it is sometimes difficult to determine the timing of injury in infants with non-cystic PVL.

	CONCLUSION

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In summary, our report suggests the possibility that the timing of injury in infants with PVL by serial EEG recordings. The information supplied by EEG readings will be useful to clarify pathogenesis and pathophysiology of PVL.

	FOOTNOTES

Received for publication Oct 12, 1998; accepted Mar 31, 1999.

Reprint requests to (F.H.) Department of Pediatrics, Okazaki City Hospital, 3-1 Goshoai, Koryuji-cho, Okazaki, Aichi, 444-8553, Japan. E-mail: ikyoku{at}quartz.ocn.ne.jp

	ABBREVIATIONS

PVL, periventricular leukomalacia; CP, cerebral palsy; EEG, electroencephalography.

	REFERENCES

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