High expression of tumor necrosis factor-α and interleukin-6 in periventricular leukomalacia,☆☆,,★★,

https://doi.org/10.1016/S0002-9378(97)70206-0Get rights and content

Abstract

Objective: Periventricular leukomalacia, a common neonatal brain white matter lesion, is a major risk factor for cerebral palsy. Subclinical chorioamnionitis is a risk factor for the development of periventricular leukomalacia, and inflammatory cytokines have been implicated as central mediators of brain injury in this disorder. To elucidate the relationship between the local expression of cytokines and periventricular leukomalacia, we studied neonatal brains to determine whether high expression of tumor necrosis factor-α, interleukin-1β, and interleukin-6 was observed in these lesions. Study design: Immunohistochemical staining for cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6) was performed in 10% formalin-fixed, paraffin-embedded brain sections of 17 cases with periventricular leukomalacia. Specimens were obtained from autopsies performed between 1987 and 1994. Brain sections from 17 cases of neonatal deaths without periventricular leukomalacia lesions matched for gestational age at birth, duration of postnatal survival, and presence or absence of infection-related morbidity were used as controls. Results: The expression of tumor necrosis factor-α, interleukin-1β, or interleukin-6 was demonstrated in 88% (15/17) of cases with and in 18% (3/17) of cases without periventricular leukomalacia (p < 0.001). Cytokines were expressed mainly in hypertrophic astrocytes and microglial cells. The expression of tumor necrosis factor-α, interleukin-1β, and interleukin-6 was identified in 82% (14/17), 29% (5/17), and 71% (12/17) of cases of periventricular leukomalacia, respectively. However, a significantly lower proportion of cases without periventricular leukomalacia expressed tumor necrosis factor-α (18%, 3/17) and interleukin-6 (6%, 1/17) than those with the disorder (p < 0.005 for each). Conclusions: Expression of tumor necrosis factor-α and interleukin-6 was observed more frequently in brain lesions with periventricular leukomalacia than in those without periventricular leukomalacia. These findings provide strong support for the hypothesis that proinflammatory cytokines play a role in the genesis of periventricular leukomalacia. (Am J Obstet Gynecol 1997;177:406-11.)

Section snippets

Study design

A case-control study was designed to compare cytokine expression in histologic sections of brains of neonates who died with and without periventricular leukomalacia. The autopsy records of the Department of Pathology at Seoul National University Children's Hospital between 1987 and 1994 were reviewed to identify cases with these lesions. Controls were obtained from cases of neonatal deaths without periventricular leukomalacia lesions over the same period of time matched for gestational age at

Results

A total of 20 cases with periventricular leukomalacia were identified during the study period. Three cases died of major congenital anomalies (chondrodysplasia [n = 1] and lung hypoplasia [n = 2]) and were excluded from the final analysis. Cytokine expression was demonstrated in the brains of all these cases with periventricular leukomalacia and major congenital anomalies.

Table I provides detailed information about the gestational age at birth, duration of survival, neonatal complications, and

Comment

Although brain white matter lesions are the most important identifiable risk factors for the development of cerebral palsy, there is a paucity of information about the molecular pathologic mechanisms responsible for this disease. In 1993 Leviton9 proposed that inflammatory cytokines released during the course of intrauterine infection may mediate the white matter damage characteristic of periventricular leukomalacia. Our data clearly indicate that antigenic expression of TNF-α and IL-6 was

References (27)

  • JQ Trounce et al.

    Periventricular leukomalacia and intraventricular hemorrhage in the preterm neonate

    Arch Dis Child

    (1986)
  • SK Sinha et al.

    Relation between periventricular haemorrhage and ischemic brain lesions diagnosed by ultrasound in very pre-term infants

    Lancet

    (1985)
  • FH Gilles et al.

    Neonatal endotoxin encephalopathy

    Ann Neurol

    (1977)
  • Cited by (0)

    From the Departments of Obstetrics and Gynecologya and Pathology,b College of Medicine, Seoul National University.

    ☆☆

    Supported by grant No. 03-96-050 from Seoul National University Hospital Research Fund.

    Dr. Romero has participated as a private citizen, not as an agent of the U.S. government or any of the universities to which he holds appointments.

    ★★

    Reprint requests: Bo Hyun Yoon, MD, PhD, Department of Obstetrics and Gynecology, College of Medicine, Seoul National University, Seoul, Korea, 110-744.

    6/1/82600

    View full text