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Elevated S100 blood level as an early indicator of intraventricular hemorrhage in preterm infants
Journal of the Neurological Sciences 170 (1999) 32–35 www.elsevier.com / locate / jns
Elevated S100 blood level as an early indicator of intraventricular hemorrhage in preterm infants: Correlation with cerebral Doppler velocimetry Diego Gazzolo a , Paola Vinesi b , Marco Bartocci a , Maria Concetta Geloso b , Wanda Bonacci a , a c b, Giovanni Serra , Kenneth G. Haglid , Fabrizio Michetti * a
Department of Neonatology, Giannina Gaslini Children’ s Hospital, I-16147 Genoa, Italy b Institute of Histology, Catholic University, I-00168 Rome, Italy c Department of Anatomy and Cell Biology, Goteborg University, S-413 -90 Goteborg, Sweden Received 19 February 1999; received in revised form 3 August 1999; accepted 9 August 1999
Abstract The aim of this study was to assess the use of S100 protein in blood as a means of identifying preterm infants at risk of intraventricular hemorrhage. In 25 preterm newborns, S100 blood concentrations were measured by an immunoradiometric assay during the first 48 h. Cerebral Doppler velocimetry waveform patterns were also tested at the time the blood sample was taken, when clinical and cerebral ultrasound scanning were still normal. Of the 25 newborns studied, 14 were controls and 11 developed intraventricular hemorrhage as revealed by ultrasound scanning more than 72 h after birth, and clinically confirmed by neurological examination on the seventh day of follow-up. S100 blood concentrations were significantly higher (P , 0.002) in infants with intraventricular hemorrhage than in control infants and also correlated significantly (r 5 0.81, P , 0.003) with the grade of hemorrhage. A significant correlation (r 5 0.70, P , 0.05) between the S100 blood concentration and the middle cerebral artery pulsatility index was also observed. The present data show that S100 blood concentrations offer a measurable parameter of brain lesion in preterm infants before a radiological assessment of hemorrhage can be performed, when clinical symptoms may be silent and preventive / therapeutic action could be especially useful. 1999 Elsevier Science B.V. All rights reserved. Keywords: S100 protein; Intraventricular hemorrhage; Preterm infants; Hemodynamic impairment; Brain distress; Biochemical marker; Blood protein
1. Introduction Perinatal asphyxia is known to constitute a risk in preterm infants, possibly leading to germinal matrix or intraventricular hemorrhage (IVH), which is currently difficult to diagnose during the first 72 h [1], despite accurate postnatal monitoring. The availability of quantitative parameters indicating subclinical lesions at a time *Corresponding author. Institute of Histology, Universita` Cattolica del S. Cuore, Largo Francesco Vito, 1, I-00168 Rome, Italy. Tel.: 139-06301-54463; fax: 139-06-305-1343. E-mail address: [email protected] (F. Michetti)
when ultrasound scanning and radiological procedures are unable to detect bleeding is important. Furthermore, quantification of the extent of the hemorrhagic lesion is important to permit the prevention and / or treatment of clinical neurological damage. The concentration in biological fluids of the S100 protein, which is a member of the calcium-binding proteins present primarily in nervous tissue [2,3], represents a well established biochemical index of brain damage [4–6]. Recently, it has also been shown to be a reliable tool to monitor brain distress in child patients [7]. The present study investigated whether S100 protein is a useful means of evaluating perinatal brain distress, which
0022-510X / 99 / $ – see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 99 )00194-X
D. Gazzolo et al. / Journal of the Neurological Sciences 170 (1999) 32 – 35
ultimately leads to IVH, in order to give early warning of subjects at risk when diagnostic tools are of no avail in detecting cerebral bleeding.
2. Materials and methods Levels of S100 in blood and standard monitoring procedures, such as cerebral ultrasound scanning, cerebral Doppler velocimetry waveform patterns and neurological examination, were performed at the same intervals during the first 48 h after birth in 25 preterm newborns. The two groups to be compared (11 IVH and 14 controls) were formed on the basis of the presence or absence of IVH as revealed by ultrasound scanning more than 72 h after birth (between 74 and 78 h) according to Papile et al. [8], and were clinically confirmed by neurological examination on the seventh day of follow-up. No statistical difference between the two groups was observed regarding the timing of tests performed (3566 h for controls and 3564 h for IVH patients, P . 0.9, n.s.). Neonatal outcomes and clinical parameters (delivery procedure, age at birth, birthweight, Apgar score at first and fifth minute, respiratory distress syndrome (RDS) according to Hyalmarsson [13], blood pH, red blood cell count, blood pressure) were recorded to monitor the general pattern of clinical condition of the newborns. The study protocol was approved by the Ethics Committee of the Giannina Gaslini Children’s Hospital, Genoa University, and the parents of the subjects examined gave informed consent. Heparin-treated blood samples taken during the first 48 h were immediately centrifuged at 900 g for 10 min, and the supernatants stored at 2708C before measurement. The S100 protein concentration was measured in all samples, using a commercially available two-site immunoradiometric assay (IRMA) kit (Sangtec 100, AB Sangtec Medical, Bromma, Sweden). This IRMA is specific for the b subunit of the protein, which is known to be predominant (80–96%) in the human brain [9,10]. Each measurement was performed in duplicate according to the manufacturer’s recommendations and the averages are reported. The limit of sensitivity of the assay was 0.2 mg / l. The precision (cv) was ,10%. Standard cerebral echography was performed by a realtime ultrasound machine (Acuson, 128SP5, USA), and a pulsed Doppler apparatus (Acuson 128SP5, USA) was used for blood flow velocity measurement of the pulsatility index (PI) in the middle cerebral artery (MCA), which was performed at the same time blood was drawn. Neurological examinations were routinely performed and the results obtained on the seventh day after birth (when sedation effects were significantly reduced) were recorded in order to confirm the diagnosis clinically. Results were classified using a qualitative approach assigning each infant to one of three diagnostic groups: normal,
33
suspect or abnormal. Infants were considered abnormal if one or more of the following neurological syndromes were present: hyper- or hypokinesia, hyper- or hypotonia, hemisyndrome, apathy syndrome, hyperexcitability syndrome, asymmetry. Infants were classified as suspect if only isolated symptoms were present [11,12]. The S100 blood concentrations and neonatal monitoring parameters of the groups examined were analysed by Mann–Whitney U two-sided test, except RDS, which was tested by Fisher’s exact test; the correlation between the blood concentrations of S100 and the MCA PI of different IVH patients was analysed by linear regression analysis. A value of P , 0.05 was considered significant.
3. Results At birth, no significant differences were observed in the two preterm groups regarding gestational age (3561 week for both groups), birthweight (22216481 g control group vs. 20646476 g IVH, P , 0.5, n.s.) and laboratory parameters, except the Apgar score at the first minute, which was significantly lower in the IVH infants (6.262 for the control group; 3.863 for the IVH group, P , 0.003), and the incidence of RDS, which was significantly higher in the IVH infants (0 / 14 vs. 6 / 11, P , 0.03). No cerebral ultrasound features or neurological signs of IVH were observed in any of the 25 monitored newborns during the first 48 h of birth. After 72 h from birth, 11 out of 24 preterm infants showed ultrasound features of IVH. On the seventh day of neurological follow-up, 10 IVH infants were classified as abnormal (hyper-hypotonia syndrome, n 5 7; hyperexcitability syndrome, n 5 3), while neurological conditions were normal in the 14 control infants. One infant with ultrasound diagnosis of IVH died of heart failure on day 4 after birth (before the seventh day of neurological followup). The levels of S100 in the blood taken from preterm infants at the time of monitoring are shown in Fig. 1. Concentrations were significantly higher (P , 0.002) in infants with IVH, as diagnosed later by common radiological procedures, than in control infants who showed no signs of hemorrhage. Among IVH patients, six subjects exhibited a hemorrhage of grade 1, four of grade 2, while the patient who died exhibited a hemorrhage of grade 4. The highest S100 concentration was detected in the infant who died, indicating a more extensive brain lesion and, in general, a significant correlation (r 5 0.81, P , 0.002) was observed between S100 concentrations and the grade of hemorrhage. Nevertheless, the majority of patients without clinically detectable hemorrhage exhibited low but detectable levels of the S100 protein, while clinically healthy infants would be expected to have unmeasurable levels of S100 [14]. In any case no significant correlation could be
34
D. Gazzolo et al. / Journal of the Neurological Sciences 170 (1999) 32 – 35
4. Discussion
Fig. 1. S100 blood concentrations in control and IVH infants with favorable (s) and unfavorable outcome (d) during the first 48 h after birth. Values are the averages of two determinations. The dotted line indicates the limit of sensitivity of the assay (0.2 mg / l); h and vertical lines are mean values of determinations in the two groups and standard deviations, respectively.
found between S100 protein levels and gestational age (r 5 0.410, P . 0.2, n.s.) Fig. 2 shows a significant correlation (r 5 0.70, P , 0.05) between the concentrations of S100 in blood and the MCA PI of different IVH patients. This parameter was drastically elevated in the patient who died, stressing the notion [15,16] that hemodynamic impairment, as revealed by MCA PI, correlates with the severity of hemorrhagic lesion leading to S100 release in these patients.
While the appearance of fetal hypoxia markers such as nucleated erythrocytes and uric acid in the blood of preterm infants with IVH has been reported [17,18], the release in the blood of brain constituents such as S100, which is a direct indicator of active cell damage in the nervous system, has not previously been detected. In addition, this brain damage indicator is significantly correlated with the degree of hemorrhage. This finding could be of importance, since it could offer a measurable parameter of the lesion before a radiological assessment of hemorrhage can be performed. Moreover, clinical symptoms at this stage may still be silent. This means that the time window for preventive / therapeutic action is expanded, with possible improvement in the final outcome for patients. The finding of low but detectable levels of the protein in a number of patients without clinically detectable hemorrhage could also be attributable to subclinical perinatal neurological distress that is undetectable by radiological procedures and may be accompanied by increased permeability of the blood / brain barrier [19]. Experimental data suggest that S100 may be released in the nervous system as a cytokine, with a neurotrophic effect at low concentrations, but exerting a neurotoxic role at high concentrations [2,20–22]. The possibility that at least part of the S100 measured in the blood of these patients derives from this process, which may be part of a pathological cascade of events accompanying parenchymal damage, should also be taken into consideration. However, since we do not at present know the local extracellular concentration of S100 at the site of the lesion or at the time it occurs, this issue cannot be solved definitively. In any case, the present data support the possibility that S100 is a direct indicator of cerebral damage caused by hemodynamic impairment in infants, as already established in adults [23,24].
Acknowledgements Partially supported by grants to F.M. and D.G. from Consiglio Nazionale delle Ricerche, and to K.G.H. from the Swedish Medical Research Council. We also thank Sangtec Medical, Bromma, Sweden, and Byk Gulden Italia, Cormano, for partially supporting this work.
References
Fig. 2. Correlation of MCA PI with S100 blood concentrations in IVH infants with favorable (s) and unfavorable outcome (d) during the first 48 h after birth by linear regression analysis (r 5 0.70, P , 0.05, n 5 11). S100 values are the averages of two measurements.
[1] Volpe JJ. Intracranial hemorrhage: germinal matrix-intraventricular hemorrhage of the premature infant. In: Volpe JJ, editor, Neurology of the newborn, Philadelphia: Saunders, 1995, pp. 403–63. [2] Fano` G, Biocca S, Fulle S, Mariggio` MA, Belia S, Calissano P. The S100: a protein family in search of a function. Prog Neurobiol (Oxford) 1995;46:71–82. [3] Zimmer D, Cornwall EH, Landar A, Song W. The S100 protein
D. Gazzolo et al. / Journal of the Neurological Sciences 170 (1999) 32 – 35
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
family: history, function and expression. Brain Res Bull 1995;37:417–29. Michetti F, Massaro A, Murazio M. The nervous system-specific S100 antigen in cerebrospinal fluid of multiple sclerosis patients. Neurosci Lett 1979;11:171–5. Michetti F, Massaro A, Russo G, Rigon G. The S100 antigen in cerebrospinal fluid as a possible index of cell injury in the nervous system. J Neurol Sci 1980;44:731–43. Persson L, Hardemark HG, Gustafsson J, Rundstrom G, MendelHartvig I, Esscher T, Pahlman S. S100 protein and neuron-specific enolase in cerebrospinal fluid and serum: markers of cell damage in human central nervous tissue. Stroke 1987;18:911–8. Gazzolo D, Vinesi P, Geloso MC, Marcelletti C, Iorio FS, Cipriani A, Marianeschi SM, Michetti F. S100 blood concentrations in children subjected to cardiopulmonary by-pass. Clin Chem 1998;44:1058–60. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birthweight less than 1,500 grams. J Pediatr 1983;103:273–7. Baudier J, Glasser N, Haglid K, Gerard D. Purification, characterization and ion binding properties of human brain S100b protein. Biochim Biophys Acta 1984;790:164–73. Jensen R, Marshak D, Anderson C, Lukas T, Watterson D. Characterization of human brain S100 protein fraction: amino acid sequence of S100b. J Neurochem 1985;45:700–5. Prechtl HFR. Assessment methods for the newborn infant: a critical evaluation. In: Stratton D, editor, Psychobiology of human newborn, Chichester: Wiley, 1982, pp. 21–52. Dijxhoorn MJ, Visser GHA, Fidler VJ, Touwen BCL, Huisjes HJ. Apgar score, meconium and acidaemia at birth in relation to neonatal neurological morbidity in term infants. Br J Obstet Gynaecol 1986;93:217–21. Hyalmarsson O. Epidemiology and classification of acute neonatal respiratory disorders. A prospective study. Obstet Gynecol 1981;155:293–6. Nygaard Ø, Langbakk B, Romner B. Age- and sex-related changes
[15] [16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
35
of S100 protein concentrations in cerebrospinal fluid and serum in patients with no previous history of neurological disorder. Clin Chem 1997;43:541–3. Ando Y, Takashima S, Takeshita K. Cerebral blood flow velocity in preterm neonates. Brain Develop 1985;7:385–91. Archer LNJ, Levene MI, Evans DH. Cerebral artery Doppler ultrasonography for prediction of outcome after perinatal asphyxia. Lancet 1986;2:1116–8. Green DW, Hendon B, Mimouni FB. Nucleated erythrocytes and intraventricular hemorrhage in preterm infants. Pediatrics 1995;96:475–8. Perlman JM, Risser R. Relationship of uric acid concentrations and severe intraventricular hemorrhage / leukomalacia in the premature infant. J Pediatr 1998;132:436–9. Wladimiroff JW, Wijngaard GW, Degani S, Noordam MJ, Eyck J, Tonge HM. Cerebral and umbilical arterial blood flow velocity waveforms in normal and intrauterine growth retarded fetuses. Obstet Gynecol 1987;69:705–9. Bhattacharyya A, Oppenheim RW, Prevette D, Moore BW, Brackenbury R, Ratner N. S100 is present in developing chicken neurons and Schwann cells and promotes neuron survival in vivo. J Neurobiol 1992;23:451–66. Haglid KG, Yang Q, Hamberger A, Bergman S, Widerberg A, Danielsen N. S100b stimulates neurite outgrowth in the rat sciatic nerve grafted with acellular muscle transplants. Brain Res 1997;753:196–201. Hu J, Ferreira A, Van Eldik LJ. S100b induces neuronal death through nitric oxide release from astrocytes. J Neurochem 1997;69:2294–301. Fognart OC, Sindic CJ, Laterre C. Particle counting immunoassay of S100 protein in serum. Possible relevance in tumors and ischemic disorders of the central nervous system. Clin Chem 1988;34:1387– 91. Westaby S, Johnsson P, Parry AJ, Blomqvist S, Solem JO, Alling C, Pillai R, Taggart DP, Grebenik C, Stahl E. Serum S100 protein: a potential marker for cerebral events during cardiopulmonary bypass. Ann Thorac Surg 1996;61:88–92.
Elevated S100 blood level as an early indicator of intraventricular hemorrhage in preterm infants: Correlation with cerebral Doppler velocimetry Diego Gazzolo a , Paola Vinesi b , Marco Bartocci a , Maria Concetta Geloso b , Wanda Bonacci a , a c b, Giovanni Serra , Kenneth G. Haglid , Fabrizio Michetti * a
Department of Neonatology, Giannina Gaslini Children’ s Hospital, I-16147 Genoa, Italy b Institute of Histology, Catholic University, I-00168 Rome, Italy c Department of Anatomy and Cell Biology, Goteborg University, S-413 -90 Goteborg, Sweden Received 19 February 1999; received in revised form 3 August 1999; accepted 9 August 1999
Abstract The aim of this study was to assess the use of S100 protein in blood as a means of identifying preterm infants at risk of intraventricular hemorrhage. In 25 preterm newborns, S100 blood concentrations were measured by an immunoradiometric assay during the first 48 h. Cerebral Doppler velocimetry waveform patterns were also tested at the time the blood sample was taken, when clinical and cerebral ultrasound scanning were still normal. Of the 25 newborns studied, 14 were controls and 11 developed intraventricular hemorrhage as revealed by ultrasound scanning more than 72 h after birth, and clinically confirmed by neurological examination on the seventh day of follow-up. S100 blood concentrations were significantly higher (P , 0.002) in infants with intraventricular hemorrhage than in control infants and also correlated significantly (r 5 0.81, P , 0.003) with the grade of hemorrhage. A significant correlation (r 5 0.70, P , 0.05) between the S100 blood concentration and the middle cerebral artery pulsatility index was also observed. The present data show that S100 blood concentrations offer a measurable parameter of brain lesion in preterm infants before a radiological assessment of hemorrhage can be performed, when clinical symptoms may be silent and preventive / therapeutic action could be especially useful. 1999 Elsevier Science B.V. All rights reserved. Keywords: S100 protein; Intraventricular hemorrhage; Preterm infants; Hemodynamic impairment; Brain distress; Biochemical marker; Blood protein
1. Introduction Perinatal asphyxia is known to constitute a risk in preterm infants, possibly leading to germinal matrix or intraventricular hemorrhage (IVH), which is currently difficult to diagnose during the first 72 h [1], despite accurate postnatal monitoring. The availability of quantitative parameters indicating subclinical lesions at a time *Corresponding author. Institute of Histology, Universita` Cattolica del S. Cuore, Largo Francesco Vito, 1, I-00168 Rome, Italy. Tel.: 139-06301-54463; fax: 139-06-305-1343. E-mail address: [email protected] (F. Michetti)
when ultrasound scanning and radiological procedures are unable to detect bleeding is important. Furthermore, quantification of the extent of the hemorrhagic lesion is important to permit the prevention and / or treatment of clinical neurological damage. The concentration in biological fluids of the S100 protein, which is a member of the calcium-binding proteins present primarily in nervous tissue [2,3], represents a well established biochemical index of brain damage [4–6]. Recently, it has also been shown to be a reliable tool to monitor brain distress in child patients [7]. The present study investigated whether S100 protein is a useful means of evaluating perinatal brain distress, which
0022-510X / 99 / $ – see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 99 )00194-X
D. Gazzolo et al. / Journal of the Neurological Sciences 170 (1999) 32 – 35
ultimately leads to IVH, in order to give early warning of subjects at risk when diagnostic tools are of no avail in detecting cerebral bleeding.
2. Materials and methods Levels of S100 in blood and standard monitoring procedures, such as cerebral ultrasound scanning, cerebral Doppler velocimetry waveform patterns and neurological examination, were performed at the same intervals during the first 48 h after birth in 25 preterm newborns. The two groups to be compared (11 IVH and 14 controls) were formed on the basis of the presence or absence of IVH as revealed by ultrasound scanning more than 72 h after birth (between 74 and 78 h) according to Papile et al. [8], and were clinically confirmed by neurological examination on the seventh day of follow-up. No statistical difference between the two groups was observed regarding the timing of tests performed (3566 h for controls and 3564 h for IVH patients, P . 0.9, n.s.). Neonatal outcomes and clinical parameters (delivery procedure, age at birth, birthweight, Apgar score at first and fifth minute, respiratory distress syndrome (RDS) according to Hyalmarsson [13], blood pH, red blood cell count, blood pressure) were recorded to monitor the general pattern of clinical condition of the newborns. The study protocol was approved by the Ethics Committee of the Giannina Gaslini Children’s Hospital, Genoa University, and the parents of the subjects examined gave informed consent. Heparin-treated blood samples taken during the first 48 h were immediately centrifuged at 900 g for 10 min, and the supernatants stored at 2708C before measurement. The S100 protein concentration was measured in all samples, using a commercially available two-site immunoradiometric assay (IRMA) kit (Sangtec 100, AB Sangtec Medical, Bromma, Sweden). This IRMA is specific for the b subunit of the protein, which is known to be predominant (80–96%) in the human brain [9,10]. Each measurement was performed in duplicate according to the manufacturer’s recommendations and the averages are reported. The limit of sensitivity of the assay was 0.2 mg / l. The precision (cv) was ,10%. Standard cerebral echography was performed by a realtime ultrasound machine (Acuson, 128SP5, USA), and a pulsed Doppler apparatus (Acuson 128SP5, USA) was used for blood flow velocity measurement of the pulsatility index (PI) in the middle cerebral artery (MCA), which was performed at the same time blood was drawn. Neurological examinations were routinely performed and the results obtained on the seventh day after birth (when sedation effects were significantly reduced) were recorded in order to confirm the diagnosis clinically. Results were classified using a qualitative approach assigning each infant to one of three diagnostic groups: normal,
33
suspect or abnormal. Infants were considered abnormal if one or more of the following neurological syndromes were present: hyper- or hypokinesia, hyper- or hypotonia, hemisyndrome, apathy syndrome, hyperexcitability syndrome, asymmetry. Infants were classified as suspect if only isolated symptoms were present [11,12]. The S100 blood concentrations and neonatal monitoring parameters of the groups examined were analysed by Mann–Whitney U two-sided test, except RDS, which was tested by Fisher’s exact test; the correlation between the blood concentrations of S100 and the MCA PI of different IVH patients was analysed by linear regression analysis. A value of P , 0.05 was considered significant.
3. Results At birth, no significant differences were observed in the two preterm groups regarding gestational age (3561 week for both groups), birthweight (22216481 g control group vs. 20646476 g IVH, P , 0.5, n.s.) and laboratory parameters, except the Apgar score at the first minute, which was significantly lower in the IVH infants (6.262 for the control group; 3.863 for the IVH group, P , 0.003), and the incidence of RDS, which was significantly higher in the IVH infants (0 / 14 vs. 6 / 11, P , 0.03). No cerebral ultrasound features or neurological signs of IVH were observed in any of the 25 monitored newborns during the first 48 h of birth. After 72 h from birth, 11 out of 24 preterm infants showed ultrasound features of IVH. On the seventh day of neurological follow-up, 10 IVH infants were classified as abnormal (hyper-hypotonia syndrome, n 5 7; hyperexcitability syndrome, n 5 3), while neurological conditions were normal in the 14 control infants. One infant with ultrasound diagnosis of IVH died of heart failure on day 4 after birth (before the seventh day of neurological followup). The levels of S100 in the blood taken from preterm infants at the time of monitoring are shown in Fig. 1. Concentrations were significantly higher (P , 0.002) in infants with IVH, as diagnosed later by common radiological procedures, than in control infants who showed no signs of hemorrhage. Among IVH patients, six subjects exhibited a hemorrhage of grade 1, four of grade 2, while the patient who died exhibited a hemorrhage of grade 4. The highest S100 concentration was detected in the infant who died, indicating a more extensive brain lesion and, in general, a significant correlation (r 5 0.81, P , 0.002) was observed between S100 concentrations and the grade of hemorrhage. Nevertheless, the majority of patients without clinically detectable hemorrhage exhibited low but detectable levels of the S100 protein, while clinically healthy infants would be expected to have unmeasurable levels of S100 [14]. In any case no significant correlation could be
34
D. Gazzolo et al. / Journal of the Neurological Sciences 170 (1999) 32 – 35
4. Discussion
Fig. 1. S100 blood concentrations in control and IVH infants with favorable (s) and unfavorable outcome (d) during the first 48 h after birth. Values are the averages of two determinations. The dotted line indicates the limit of sensitivity of the assay (0.2 mg / l); h and vertical lines are mean values of determinations in the two groups and standard deviations, respectively.
found between S100 protein levels and gestational age (r 5 0.410, P . 0.2, n.s.) Fig. 2 shows a significant correlation (r 5 0.70, P , 0.05) between the concentrations of S100 in blood and the MCA PI of different IVH patients. This parameter was drastically elevated in the patient who died, stressing the notion [15,16] that hemodynamic impairment, as revealed by MCA PI, correlates with the severity of hemorrhagic lesion leading to S100 release in these patients.
While the appearance of fetal hypoxia markers such as nucleated erythrocytes and uric acid in the blood of preterm infants with IVH has been reported [17,18], the release in the blood of brain constituents such as S100, which is a direct indicator of active cell damage in the nervous system, has not previously been detected. In addition, this brain damage indicator is significantly correlated with the degree of hemorrhage. This finding could be of importance, since it could offer a measurable parameter of the lesion before a radiological assessment of hemorrhage can be performed. Moreover, clinical symptoms at this stage may still be silent. This means that the time window for preventive / therapeutic action is expanded, with possible improvement in the final outcome for patients. The finding of low but detectable levels of the protein in a number of patients without clinically detectable hemorrhage could also be attributable to subclinical perinatal neurological distress that is undetectable by radiological procedures and may be accompanied by increased permeability of the blood / brain barrier [19]. Experimental data suggest that S100 may be released in the nervous system as a cytokine, with a neurotrophic effect at low concentrations, but exerting a neurotoxic role at high concentrations [2,20–22]. The possibility that at least part of the S100 measured in the blood of these patients derives from this process, which may be part of a pathological cascade of events accompanying parenchymal damage, should also be taken into consideration. However, since we do not at present know the local extracellular concentration of S100 at the site of the lesion or at the time it occurs, this issue cannot be solved definitively. In any case, the present data support the possibility that S100 is a direct indicator of cerebral damage caused by hemodynamic impairment in infants, as already established in adults [23,24].
Acknowledgements Partially supported by grants to F.M. and D.G. from Consiglio Nazionale delle Ricerche, and to K.G.H. from the Swedish Medical Research Council. We also thank Sangtec Medical, Bromma, Sweden, and Byk Gulden Italia, Cormano, for partially supporting this work.
References
Fig. 2. Correlation of MCA PI with S100 blood concentrations in IVH infants with favorable (s) and unfavorable outcome (d) during the first 48 h after birth by linear regression analysis (r 5 0.70, P , 0.05, n 5 11). S100 values are the averages of two measurements.
[1] Volpe JJ. Intracranial hemorrhage: germinal matrix-intraventricular hemorrhage of the premature infant. In: Volpe JJ, editor, Neurology of the newborn, Philadelphia: Saunders, 1995, pp. 403–63. [2] Fano` G, Biocca S, Fulle S, Mariggio` MA, Belia S, Calissano P. The S100: a protein family in search of a function. Prog Neurobiol (Oxford) 1995;46:71–82. [3] Zimmer D, Cornwall EH, Landar A, Song W. The S100 protein
D. Gazzolo et al. / Journal of the Neurological Sciences 170 (1999) 32 – 35
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
family: history, function and expression. Brain Res Bull 1995;37:417–29. Michetti F, Massaro A, Murazio M. The nervous system-specific S100 antigen in cerebrospinal fluid of multiple sclerosis patients. Neurosci Lett 1979;11:171–5. Michetti F, Massaro A, Russo G, Rigon G. The S100 antigen in cerebrospinal fluid as a possible index of cell injury in the nervous system. J Neurol Sci 1980;44:731–43. Persson L, Hardemark HG, Gustafsson J, Rundstrom G, MendelHartvig I, Esscher T, Pahlman S. S100 protein and neuron-specific enolase in cerebrospinal fluid and serum: markers of cell damage in human central nervous tissue. Stroke 1987;18:911–8. Gazzolo D, Vinesi P, Geloso MC, Marcelletti C, Iorio FS, Cipriani A, Marianeschi SM, Michetti F. S100 blood concentrations in children subjected to cardiopulmonary by-pass. Clin Chem 1998;44:1058–60. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birthweight less than 1,500 grams. J Pediatr 1983;103:273–7. Baudier J, Glasser N, Haglid K, Gerard D. Purification, characterization and ion binding properties of human brain S100b protein. Biochim Biophys Acta 1984;790:164–73. Jensen R, Marshak D, Anderson C, Lukas T, Watterson D. Characterization of human brain S100 protein fraction: amino acid sequence of S100b. J Neurochem 1985;45:700–5. Prechtl HFR. Assessment methods for the newborn infant: a critical evaluation. In: Stratton D, editor, Psychobiology of human newborn, Chichester: Wiley, 1982, pp. 21–52. Dijxhoorn MJ, Visser GHA, Fidler VJ, Touwen BCL, Huisjes HJ. Apgar score, meconium and acidaemia at birth in relation to neonatal neurological morbidity in term infants. Br J Obstet Gynaecol 1986;93:217–21. Hyalmarsson O. Epidemiology and classification of acute neonatal respiratory disorders. A prospective study. Obstet Gynecol 1981;155:293–6. Nygaard Ø, Langbakk B, Romner B. Age- and sex-related changes
[15] [16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
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