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Table of Contents
Vol. 101, No. 1, 2012
Issue release date: December 2011
Section title: Review
Free Access
Neonatology 2012;101:1–7
(DOI:10.1159/000323498)

Biomarkers in Neonatal Posthemorrhagic Hydrocephalus

Merhar S.
Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
email Corresponding Author

Abstract

Posthemorrhagic hydrocephalus (PHH) is a rare but serious outcome among premature babies in the NICU, with consequences including mortality and severe neurodevelopmental disabilities. The causes of PHH are still not entirely understood, and its prevention and treatment are controversial. Various cerebrospinal fluid biomarkers have been studied in infants with PHH in order to recognize the causes, diagnose brain injury, and predict neurodevelopmental outcomes. This systematic review summarizes studies on biomarkers of extracellular matrix activity, fibrinolysis/coagulation, hypoxia/cell death, and inflammation in the cerebrospinal fluid of infants with PHH.

© 2011 S. Karger AG, Basel


  

Key Words

  • Posthemorrhagic hydrocephalus
  • Posthemorrhagic ventricular dilation
  • Biomarker

References

  1. Volpe JJ: Neurology of the Newborn, ed 5. Amsterdam, Elsevier Health Sciences, 2008.
  2. Batton DG, Holtrop P, DeWitte D, Pryce C, Roberts C: Current gestational age-related incidence of major intraventricular hemorrhage. J Pediatr 1994;125:623–625.
  3. Heuchan AM, Evans N, Henderson Smart DJ, Simpson JM: Perinatal risk factors for major intraventricular haemorrhage in the Australian and New Zealand Neonatal Network, 1995–97. Arch Dis Child Fetal Neonatal Ed 2002;86:F86–F90.
  4. Sheth RD: Trends in incidence and severity of intraventricular hemorrhage. J Child Neurol 1998;13:261–264.
  5. Murphy BP, Inder TE, Rooks V, Taylor GA, Anderson NJ, Mogridge N, et al: Posthaemorrhagic ventricular dilatation in the premature infant: natural history and predictors of outcome. Arch Dis Child Fetal Neonatal Ed 2002;87:F37–F41.
  6. Allan WC, Dransfield DA, Tito AM: Ventricular dilation following periventricular-intraventricular hemorrhage: outcome at age 1 year. Pediatrics 1984;73:158–162.
  7. Davis SL, Tooley WH, Hunt JV: Developmental outcome following posthemorrhagic hydrocephalus in preterm infants. Comparison of twins discordant for hydrocephalus. Am J Dis Child 1987;141:1170–1174.
  8. Sasidharan P, Marquez E, Dizon E, Sridhar CV: Developmental outcome of infants with severe intracranial-intraventricular hemorrhage and hydrocephalus with and without ventriculoperitoneal shunt. Childs Nerv Syst 1986;2:149–152.
  9. du Plessis AJ: Posthemorrhagic hydrocephalus and brain injury in the preterm infant: dilemmas in diagnosis and management. Semin Pediatr Neurol 1998;5:161–179.
  10. Whitelaw A: Intraventricular haemorrhage and posthaemorrhagic hydrocephalus: pathogenesis, prevention and future interventions. Semin Neonatol 2001;6:135–146.
  11. Galbreath E, Kim SJ, Park K, Brenner M, Messing A: Overexpression of TGF-beta 1 in the central nervous system of transgenic mice results in hydrocephalus. J Neuropathol Exp Neurol 1995;54:339–349.
  12. Whitelaw A, Christie S, Pople I: Transforming growth factor-beta1: a possible signal molecule for posthemorrhagic hydrocephalus? Pediatr Res 1999;46:576–580.
  13. Heep A, Stoffel-Wagner B, Bartmann P, Benseler S, Schaller C, Groneck P, et al: Vascular endothelial growth factor and transforming growth factor-beta1 are highly expressed in the cerebrospinal fluid of premature infants with posthemorrhagic hydrocephalus. Pediatr Res 2004;56:768–774.
  14. Heep A, Bartmann P, Stoffel-Wagner B, Bos A, Hoving E, Brouwer O, et al: Cerebrospinal fluid obstruction and malabsorption in human neonatal hydrocephaly. Childs Nerv Syst 2006;22:1249–1255.

    External Resources

  15. Chow LC, Soliman A, Zandian M, Danielpour M, Krueger RC Jr: Accumulation of transforming growth factor-beta2 and nitrated chondroitin sulfate proteoglycans in cerebrospinal fluid correlates with poor neurologic outcome in preterm hydrocephalus. Biol Neonate 2005;88:1–11.
  16. Lipina R, Reguli S, Novackova L, Podesvova H, Brichtova E: Relation between TGF-beta 1 levels in cerebrospinal fluid and ETV outcome in premature newborns with posthemorrhagic hydrocephalus. Childs Nerv Syst 2010;26:333–341.
  17. Heep A, Stoffel-Wagner B, Soditt V, Aring C, Groneck P, Bartmann P: Procollagen I C-propeptide in the cerebrospinal fluid of neonates with posthaemorrhagic hydrocephalus. Arch Dis Child Fetal Neonatal Ed 2002;87:F34–F36.
  18. Okamoto T, Takahashi S, Nakamura E, Nagaya K, Hayashi T, Shirai M, et al: Matrix metalloproteinases in infants with posthemorrhagic hydrocephalus. Early Hum Dev 2008;84:137–139.
  19. Koehne P, Hochhaus F, Felderhoff-Mueser U, Ring-Mrozik E, Obladen M, Buhrer C: Vascular endothelial growth factor and erythropoietin concentrations in cerebrospinal fluid of children with hydrocephalus. Childs Nerv Syst 2002;18:137–141.

    External Resources

  20. Whitelaw A, Odd DE: Intraventricular streptokinase after intraventricular hemorrhage in newborn infants. Cochrane Database Syst Rev 2007; CD000498.
  21. Whitelaw A, Evans D, Carter M, Thoresen M, Wroblewska J, Mandera M, et al: Randomized clinical trial of prevention of hydrocephalus after intraventricular hemorrhage in preterm infants: brain-washing versus tapping fluid. Pediatrics 2007;119:e1071–e1078.
  22. Hansen AR, Lapp C, Brugnara C: Plasminogen activator inhibitor-1: defining characteristics in the cerebrospinal fluid of newborns. J Pediatr 2000;137:132–134.
  23. Hansen A, Whitelaw A, Lapp C, Brugnara C: Cerebrospinal fluid plasminogen activator inhibitor-1: a prognostic factor in posthaemorrhagic hydrocephalus. Acta Paediatr 1997;86:995–998.
  24. Whitelaw A, Mowinckel MC, Fellman V, Abildgaard U: Endogenous tissue plasminogen activator in neonatal cerebrospinal fluid. Eur J Pediatr 1996;155:117–119.
  25. Whitelaw A: Endogenous fibrinolysis in neonatal cerebrospinal fluid. Eur J Pediatr 1993;152:928–930.
  26. Whitelaw A, Creighton L, Gaffney P: Fibrinolysis in cerebrospinal fluid after intraventricular haemorrhage. Arch Dis Child 1991;66:808–809.
  27. Reinhold A, Zhang J, Gessner R, Felderhoff-Mueser U, Obladen M, Dame C: High thrombopoietin concentrations in the cerebrospinal fluid of neonates with sepsis and intraventricular hemorrhage may contribute to brain damage. J Interferon Cytokine Res 2007;27:137–145.
  28. Bejar R, Saugstad OD, James H, Gluck L: Increased hypoxanthine concentrations in cerebrospinal fluid of infants with hydrocephalus. J Pediatr 1983;103:44–48.
  29. Savman K, Nilsson UA, Blennow M, Kjellmer I, Whitelaw A: Non-protein-bound iron is elevated in cerebrospinal fluid from preterm infants with posthemorrhagic ventricular dilatation. Pediatr Res 2001;49:208–212.
  30. Felderhoff-Mueser U, Buhrer C, Groneck P, Obladen M, Bartmann P, Heep A: Soluble Fas (CD95/Apo-1), soluble Fas ligand, and activated caspase 3 in the cerebrospinal fluid of infants with posthemorrhagic and nonhemorrhagic hydrocephalus. Pediatr Res 2003;54:659–664.
  31. Whitelaw A, Rosengren L, Blennow M: Brain specific proteins in posthaemorrhagic ventricular dilatation. Arch Dis Child Fetal Neonatal Ed 2001;84:F90–F91.
  32. Savman K, Blennow M, Hagberg H, Tarkowski E, Thoresen M, Whitelaw A: Cytokine response in cerebrospinal fluid from preterm infants with posthaemorrhagic ventricular dilatation. Acta Paediatr 2002;91:1357–1363.
  33. Schmitz T, Heep A, Groenendaal F, Huseman D, Kie S, Bartmann P, et al: Interleukin-1beta, interleukin-18, and interferon-gamma expression in the cerebrospinal fluid of premature infants with posthemorrhagic hydrocephalus – markers of white matter damage? Pediatr Res 2007;61:722–726.
  34. White RP, Leffler CW, Bada HS: Eicosanoid levels in CSF of premature infants with posthemorrhagic hydrocephalus. Am J Med Sci 1990;299:230–235.
  35. Whitelaw A, Jary S, Kmita G, Wroblewska J, Musialik-Swietlinska E, Mandera M, et al: Randomized trial of drainage, irrigation and fibrinolytic therapy for premature infants with posthemorrhagic ventricular dilatation: developmental outcome at 2 years. Pediatrics 2010;125:e852–e858.

    External Resources

  

Author Contacts

Stephanie Merhar, MD
Division of Neonatology, Cincinnati Children’s Hospital
3333 Burnet Ave ML 7009
Cincinnati, OH 45229 (USA)
Tel. +1 513 257 7749, E-Mail stephanie.merhar@cchmc.org

  

Article Information

Received: October 7, 2010
Accepted after revision: December 9, 2010
Published online: July 27, 2011
Number of Print Pages : 7
Number of Figures : 0, Number of Tables : 0, Number of References : 35

  

Publication Details

Neonatology (Fetal and Neonatal Research)

Vol. 101, No. 1, Year 2012 (Cover Date: December 2011)

Journal Editor: Halliday H.L. (Belfast), Speer C.P. (Würzburg)
ISSN: 1661-7800 (Print), eISSN: 1661-7819 (Online)

For additional information: http://www.karger.com/NEO


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Posthemorrhagic hydrocephalus (PHH) is a rare but serious outcome among premature babies in the NICU, with consequences including mortality and severe neurodevelopmental disabilities. The causes of PHH are still not entirely understood, and its prevention and treatment are controversial. Various cerebrospinal fluid biomarkers have been studied in infants with PHH in order to recognize the causes, diagnose brain injury, and predict neurodevelopmental outcomes. This systematic review summarizes studies on biomarkers of extracellular matrix activity, fibrinolysis/coagulation, hypoxia/cell death, and inflammation in the cerebrospinal fluid of infants with PHH.

© 2011 S. Karger AG, Basel


  

Author Contacts

Stephanie Merhar, MD
Division of Neonatology, Cincinnati Children’s Hospital
3333 Burnet Ave ML 7009
Cincinnati, OH 45229 (USA)
Tel. +1 513 257 7749, E-Mail stephanie.merhar@cchmc.org

  

Article Information

Received: October 7, 2010
Accepted after revision: December 9, 2010
Published online: July 27, 2011
Number of Print Pages : 7
Number of Figures : 0, Number of Tables : 0, Number of References : 35

  

Publication Details

Neonatology (Fetal and Neonatal Research)

Vol. 101, No. 1, Year 2012 (Cover Date: December 2011)

Journal Editor: Halliday H.L. (Belfast), Speer C.P. (Würzburg)
ISSN: 1661-7800 (Print), eISSN: 1661-7819 (Online)

For additional information: http://www.karger.com/NEO


Article / Publication Details

First-Page Preview
Abstract of Review

Received: 10/7/2010
Accepted: 12/9/2010
Published online: 7/27/2011
Issue release date: December 2011

Number of Print Pages: 7
Number of Figures: 0
Number of Tables: 0

ISSN: 1661-7800 (Print)
eISSN: 1661-7819 (Online)

For additional information: http://www.karger.com/NEO


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Volpe JJ: Neurology of the Newborn, ed 5. Amsterdam, Elsevier Health Sciences, 2008.
  2. Batton DG, Holtrop P, DeWitte D, Pryce C, Roberts C: Current gestational age-related incidence of major intraventricular hemorrhage. J Pediatr 1994;125:623–625.
  3. Heuchan AM, Evans N, Henderson Smart DJ, Simpson JM: Perinatal risk factors for major intraventricular haemorrhage in the Australian and New Zealand Neonatal Network, 1995–97. Arch Dis Child Fetal Neonatal Ed 2002;86:F86–F90.
  4. Sheth RD: Trends in incidence and severity of intraventricular hemorrhage. J Child Neurol 1998;13:261–264.
  5. Murphy BP, Inder TE, Rooks V, Taylor GA, Anderson NJ, Mogridge N, et al: Posthaemorrhagic ventricular dilatation in the premature infant: natural history and predictors of outcome. Arch Dis Child Fetal Neonatal Ed 2002;87:F37–F41.
  6. Allan WC, Dransfield DA, Tito AM: Ventricular dilation following periventricular-intraventricular hemorrhage: outcome at age 1 year. Pediatrics 1984;73:158–162.
  7. Davis SL, Tooley WH, Hunt JV: Developmental outcome following posthemorrhagic hydrocephalus in preterm infants. Comparison of twins discordant for hydrocephalus. Am J Dis Child 1987;141:1170–1174.
  8. Sasidharan P, Marquez E, Dizon E, Sridhar CV: Developmental outcome of infants with severe intracranial-intraventricular hemorrhage and hydrocephalus with and without ventriculoperitoneal shunt. Childs Nerv Syst 1986;2:149–152.
  9. du Plessis AJ: Posthemorrhagic hydrocephalus and brain injury in the preterm infant: dilemmas in diagnosis and management. Semin Pediatr Neurol 1998;5:161–179.
  10. Whitelaw A: Intraventricular haemorrhage and posthaemorrhagic hydrocephalus: pathogenesis, prevention and future interventions. Semin Neonatol 2001;6:135–146.
  11. Galbreath E, Kim SJ, Park K, Brenner M, Messing A: Overexpression of TGF-beta 1 in the central nervous system of transgenic mice results in hydrocephalus. J Neuropathol Exp Neurol 1995;54:339–349.
  12. Whitelaw A, Christie S, Pople I: Transforming growth factor-beta1: a possible signal molecule for posthemorrhagic hydrocephalus? Pediatr Res 1999;46:576–580.
  13. Heep A, Stoffel-Wagner B, Bartmann P, Benseler S, Schaller C, Groneck P, et al: Vascular endothelial growth factor and transforming growth factor-beta1 are highly expressed in the cerebrospinal fluid of premature infants with posthemorrhagic hydrocephalus. Pediatr Res 2004;56:768–774.
  14. Heep A, Bartmann P, Stoffel-Wagner B, Bos A, Hoving E, Brouwer O, et al: Cerebrospinal fluid obstruction and malabsorption in human neonatal hydrocephaly. Childs Nerv Syst 2006;22:1249–1255.

    External Resources

  15. Chow LC, Soliman A, Zandian M, Danielpour M, Krueger RC Jr: Accumulation of transforming growth factor-beta2 and nitrated chondroitin sulfate proteoglycans in cerebrospinal fluid correlates with poor neurologic outcome in preterm hydrocephalus. Biol Neonate 2005;88:1–11.
  16. Lipina R, Reguli S, Novackova L, Podesvova H, Brichtova E: Relation between TGF-beta 1 levels in cerebrospinal fluid and ETV outcome in premature newborns with posthemorrhagic hydrocephalus. Childs Nerv Syst 2010;26:333–341.
  17. Heep A, Stoffel-Wagner B, Soditt V, Aring C, Groneck P, Bartmann P: Procollagen I C-propeptide in the cerebrospinal fluid of neonates with posthaemorrhagic hydrocephalus. Arch Dis Child Fetal Neonatal Ed 2002;87:F34–F36.
  18. Okamoto T, Takahashi S, Nakamura E, Nagaya K, Hayashi T, Shirai M, et al: Matrix metalloproteinases in infants with posthemorrhagic hydrocephalus. Early Hum Dev 2008;84:137–139.
  19. Koehne P, Hochhaus F, Felderhoff-Mueser U, Ring-Mrozik E, Obladen M, Buhrer C: Vascular endothelial growth factor and erythropoietin concentrations in cerebrospinal fluid of children with hydrocephalus. Childs Nerv Syst 2002;18:137–141.

    External Resources

  20. Whitelaw A, Odd DE: Intraventricular streptokinase after intraventricular hemorrhage in newborn infants. Cochrane Database Syst Rev 2007; CD000498.
  21. Whitelaw A, Evans D, Carter M, Thoresen M, Wroblewska J, Mandera M, et al: Randomized clinical trial of prevention of hydrocephalus after intraventricular hemorrhage in preterm infants: brain-washing versus tapping fluid. Pediatrics 2007;119:e1071–e1078.
  22. Hansen AR, Lapp C, Brugnara C: Plasminogen activator inhibitor-1: defining characteristics in the cerebrospinal fluid of newborns. J Pediatr 2000;137:132–134.
  23. Hansen A, Whitelaw A, Lapp C, Brugnara C: Cerebrospinal fluid plasminogen activator inhibitor-1: a prognostic factor in posthaemorrhagic hydrocephalus. Acta Paediatr 1997;86:995–998.
  24. Whitelaw A, Mowinckel MC, Fellman V, Abildgaard U: Endogenous tissue plasminogen activator in neonatal cerebrospinal fluid. Eur J Pediatr 1996;155:117–119.
  25. Whitelaw A: Endogenous fibrinolysis in neonatal cerebrospinal fluid. Eur J Pediatr 1993;152:928–930.
  26. Whitelaw A, Creighton L, Gaffney P: Fibrinolysis in cerebrospinal fluid after intraventricular haemorrhage. Arch Dis Child 1991;66:808–809.
  27. Reinhold A, Zhang J, Gessner R, Felderhoff-Mueser U, Obladen M, Dame C: High thrombopoietin concentrations in the cerebrospinal fluid of neonates with sepsis and intraventricular hemorrhage may contribute to brain damage. J Interferon Cytokine Res 2007;27:137–145.
  28. Bejar R, Saugstad OD, James H, Gluck L: Increased hypoxanthine concentrations in cerebrospinal fluid of infants with hydrocephalus. J Pediatr 1983;103:44–48.
  29. Savman K, Nilsson UA, Blennow M, Kjellmer I, Whitelaw A: Non-protein-bound iron is elevated in cerebrospinal fluid from preterm infants with posthemorrhagic ventricular dilatation. Pediatr Res 2001;49:208–212.
  30. Felderhoff-Mueser U, Buhrer C, Groneck P, Obladen M, Bartmann P, Heep A: Soluble Fas (CD95/Apo-1), soluble Fas ligand, and activated caspase 3 in the cerebrospinal fluid of infants with posthemorrhagic and nonhemorrhagic hydrocephalus. Pediatr Res 2003;54:659–664.
  31. Whitelaw A, Rosengren L, Blennow M: Brain specific proteins in posthaemorrhagic ventricular dilatation. Arch Dis Child Fetal Neonatal Ed 2001;84:F90–F91.
  32. Savman K, Blennow M, Hagberg H, Tarkowski E, Thoresen M, Whitelaw A: Cytokine response in cerebrospinal fluid from preterm infants with posthaemorrhagic ventricular dilatation. Acta Paediatr 2002;91:1357–1363.
  33. Schmitz T, Heep A, Groenendaal F, Huseman D, Kie S, Bartmann P, et al: Interleukin-1beta, interleukin-18, and interferon-gamma expression in the cerebrospinal fluid of premature infants with posthemorrhagic hydrocephalus – markers of white matter damage? Pediatr Res 2007;61:722–726.
  34. White RP, Leffler CW, Bada HS: Eicosanoid levels in CSF of premature infants with posthemorrhagic hydrocephalus. Am J Med Sci 1990;299:230–235.
  35. Whitelaw A, Jary S, Kmita G, Wroblewska J, Musialik-Swietlinska E, Mandera M, et al: Randomized trial of drainage, irrigation and fibrinolytic therapy for premature infants with posthemorrhagic ventricular dilatation: developmental outcome at 2 years. Pediatrics 2010;125:e852–e858.

    External Resources