J Neurol Surg A Cent Eur Neurosurg 2013; 74(05): 279-284
DOI: 10.1055/s-0033-1342929
Original Article
Georg Thieme Verlag KG Stuttgart · New York

TGF Beta1 and TGF Beta2 and Their Role in Posthemorrhagic Hydrocephalus Following SAH and IVH

Stefanie Kaestner
1   Department of Neurosurgery, Klinikum Kassel, Kassel, Germany
Ioannis Dimitriou
2   Department of General Surgery, Alfried-Krupp-Krankenhaus, Essen, Germany
› Author Affiliations
Further Information

Publication History

17 March 2012

25 November 2012

Publication Date:
20 May 2013 (online)


Objective Posthemorrhagic hydrocephalus (pHC) is a serious complication following subarachnoid hemorrhage (SAH) and intraventricular hemorrhage (IVH). Besides known clinical predictors, different cytokines have drawn attention to the development of chronic hydrocephalus. Transforming growth factor (TGF) β1 and TGF β2 are involved in fibrogenesis, scar formation, cell survival, and tissue differentiation and may play a role in the occurrence of pHC. TGF β1 is stored in platelets in large amount and is released in the cerebrospinal fluid (CSF) after SAH and IVH. Both TGF β1 and TGF β2 can be expressed by various intracranial cells.

Methods TGF β1 and β2 were measured in CSF and blood samples of 42 patients with SAH or IVH with acute hydrocephalus during the first 10 days after ictus. Furthermore, albumin was measured in CSF as an indicator for the amount of blood. Patients were categorized as developing pHC requiring shunt treatment or not-developing pHC within 6 months.

Results After adjusting for age, SAH resulted significantly more often in pHC than did IVH. Plasma levels of TGF β1 showed a marked increase over time, whereas CSF levels of TGF β1 constantly decreased. The time course of TGF β1 and albumin in CSF was paralleled and did not correlate with the development of shunt dependent pHC. Also, TGF β1 plasma concentrations did not correlate with shunt dependent pHC. TGF β2 concentrations in plasma showed stable values over time without any variations. TGF β2 in CSF described a parabolic course with a peak at day 6 after ictus. No correlation was found concerning TGF β2 in plasma or CSF and shunt dependent pHC.

Conclusion TGF β1 in CSF is derived by platelets from the cisternal or ventricular clot. TGF β2 in CSF is derived as a general reaction of traumatized brain tissue. These data do not confirm a crucial role of TGF β1 and TGF β2 release in the development of pHC.

  • References

  • 1 van Gijn J, Hijdra A, Wijdicks EF, Vermeulen M, van Crevel H. Acute hydrocephalus after aneurysmal subarachnoid hemorrhage. J Neurosurg 1985; 63: 355-362
  • 2 Border WA, Noble NA. Transforming growth factor beta in tissue fibrosis. N Engl J Med 1994; 331: 1286-1292
  • 3 Border WA, Ruoslahti E. Transforming growth factor-beta in disease: the dark side of tissue repair. J Clin Invest 1992; 90: 1-7
  • 4 Böttner M, Krieglstein K, Unsicker K. The transforming growth factor-betas: structure, signaling, and roles in nervous system development and functions. J Neurochem 2000; 75: 2227-2240
  • 5 Unsicker K, Flanders KC, Cissel DS, Lafyatis R, Sporn MB. Transforming growth factor beta isoforms in the adult rat central and peripheral nervous system. Neuroscience 1991; 44: 613-625
  • 6 Unsicker K, Krieglstein K. Co-activation of TGF-ss and cytokine signaling pathways are required for neurotrophic functions. Cytokine Growth Factor Rev 2000; 11: 97-102
  • 7 Johnson MD, Gold LI, Moses HL. Evidence for transforming growth factor-beta expression in human leptomeningeal cells and transforming growth factor-beta-like activity in human cerebrospinal fluid. Lab Invest 1992; 67: 360-368
  • 8 Flanders KC, Ren RF, Lippa CF. Transforming growth factor-betas in neurodegenerative disease. Prog Neurobiol 1998; 54: 71-85
  • 9 Assoian RK, Komoriya A, Meyers CA, Miller DM, Sporn MB. Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization. J Biol Chem 1983; 258: 7155-7160
  • 10 Flood C, Akinwunmi J, Lagord C , et al. Transforming growth factor-beta1 in the cerebrospinal fluid of patients with subarachnoid hemorrhage: titers derived from exogenous and endogenous sources. J Cereb Blood Flow Metab 2001; 21: 157-162
  • 11 Motohashi O, Suzuki M, Yanai N, Umezawa K, Shida N, Yoshimoto T. Thrombin and TGF-beta promote human leptomeningeal cell proliferation in vitro. Neurosci Lett 1995; 190: 105-108
  • 12 Kanaji M, Tada T, Kobayashi S. A murine model of communicating hydrocephalus: Role of TGF-beta1. J Clin Neurosci 1997; 4: 51-56
  • 13 Tada T, Kanaji M, Kobayashi S. Induction of communicating hydrocephalus in mice by intrathecal injection of human recombinant transforming growth factor-beta 1. J Neuroimmunol 1994; 50: 153-158
  • 14 Hayashi N, Leifer DW, Cohen AR. Chronologic changes of cerebral ventricular size in a transgenic model of hydrocephalus. Pediatr Neurosurg 2000; 33: 182-187
  • 15 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
  • 16 Flanders KC, Lüdecke G, Engels S , et al. Localization and actions of transforming growth factor-beta s in the embryonic nervous system. Development 1991; 113: 183-191
  • 17 Krieglstein K, Henheik P, Farkas L , et al. Glial cell line-derived neurotrophic factor requires transforming growth factor-beta for exerting its full neurotrophic potential on peripheral and CNS neurons. J Neurosci 1998; 18: 9822-9834
  • 18 Krieglstein K, Strelau J, Schobe A , et al. Transforming growth factor beta and the regulation of neuron survival and death. J Physiol 2002; 96: 25-30
  • 19 Stoll G, Schroeter M, Jander S , et al. Lesion-associated expression of transforming growth factor-beta-2 in the rat nervous system: evidence for down-regulating the phagocytic activity of microglia and macrophages. Brain Pathol 2004; 14: 51-58
  • 20 Logan A, Berry M, Gonzalez AM, Frautschy SA, Sporn MB, Baird A. Effects of transforming growth factor beta 1 on scar production in the injured central nervous system of the rat. Eur J Neurosci 1994; 6: 355-363
  • 21 Logan A, Frautschy SA, Gonzalez AM, Sporn MB, Baird A. Enhanced expression of transforming growth factor beta 1 in the rat brain after a localized cerebral injury. Brain Res 1992; 587: 216-225
  • 22 Logan A, Green J, Hunter A, Jackson R, Berry M. Inhibition of glial scarring in the injured rat brain by a recombinant human monoclonal antibody to transforming growth factor-beta2. Eur J Neurosci 1999; 11: 2367-2374
  • 23 Gaetani P, Tartara F, Pignatti P, Tancioni F, Rodriguez y Baena R, De Benedetti F. Cisternal CSF levels of cytokines after subarachnoid hemorrhage. Neurol Res 1998; 20: 337-342
  • 24 Chow LC, Soliman A, Zandian M, Danielpour M, Krueger Jr RC. 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
  • 25 Whitelaw A, Christie S, Pople I. TGF-β1: a possible Signal molecule for posthemorrhagic hydrocephalus. Pediatr Res 1999; 46: 576-580
  • 26 Kitazawa K, Tada T. Elevation of transforming growth factor-beta 1 level in cerebrospinal fluid of patients with communicating hydrocephalus after subarachnoid hemorrhage. Stroke 1994; 25: 1400-1404
  • 27 Lipina R, Reguli S, Novácková L, Podesvová H, Brichtová 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
  • 28 Graff-Radford NR, Torner J, Adams Jr HP , et al. Factors associated with hydrocepalus after subarachnoid haemorrhage. A report of the cooperative aneurysm study. Arch Neurol 1989; 85: 410-418
  • 29 Kolluri VR, Sengupta RP. Symptomatic hydrocephalus following aneurysmal subarachnoid hemorrhage. Surg Neurol 1984; 21: 402-404
  • 30 Ljunggren B, Säveland H, Brandt L. Causes of unfavorable outcome after early aneurysm operation. Neurosurgery 1983; 13: 629-633
  • 31 Ohwaki K, Yano E, Nakagomi T, Tamura A. Relationship between shunt-dependent hydrocephalus after subarachnoid haemorrhage and duration of cerebrospinal fluid drainage. Br J Neurosurg 2004; 18: 130-134
  • 32 Pietilä TA, Heimberger KC, Palleske H, Brock M. Influence of aneurysm location on the development of chronic hydrocephalus following SAH. Acta Neurochir (Wien) 1995; 137: 70-73
  • 33 Ropper AH, Zervas NT. Outcome 1 year after SAH from cerebral aneurysm. Management morbidity, mortality, and functional status in 112 consecutive good-risk patients. J Neurosurg 1984; 60: 909-915
  • 34 Dorai Z, Hynan LS, Kopitnik TA, Samson D. Factors related to hydrocephalus after aneurysmal subarachnoid hemorrhage. Neurosurgery 2003; 52: 763-769 , discussion 769–771
  • 35 Brisman JL, Berenstein A. Factors related to hydrocephalus after aneurysmal subarachnoid hemorrhage. Neurosurgery 2004; 54: 1031
  • 36 Brisman JL, Song JK, Newell DW. Cerebral aneurysms. N Engl J Med 2006; 355: 928-939
  • 37 Jartti P, Karttunen A, Jartti A, Ukkola V, Sajanti J, Pyhtinen J. Factors related to acute hydrocephalus after subarachnoid hemorrhage. Acta Radiol 2004; 45: 333-339
  • 38 Juvela S. Riskfactors for impaired outcome after spontanous intracerebral haemorrhage. Arch Neurol 1995; 52: 1193-1200
  • 39 Mehta V, Holness RO, Connolly K, Walling S, Hall R. Acute hydrocephalus following aneurysmal subarachnoid hemorrhage. Can J Neurol Sci 1996; 23: 40-45
  • 40 de Oliveira JG, Beck J, Setzer M , et al. Risk of shunt-dependent hydrocephalus after occlusion of ruptured intracranial aneurysms by surgical clipping or endovascular coiling: a single-institution series and meta-analysis. Neurosurgery 2007; 61: 924-933 , discussion 933–934
  • 41 Rincon F, Gordon E, Starke RM , et al. Predictors of long-term shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage. Clinical article. J Neurosurg 2010; 113: 774-780
  • 42 Vale FL, Bradley EL, Fisher III WS. The relationship of subarachnoid hemorrhage and the need for postoperative shunting. J Neurosurg 1997; 86: 462-466
  • 43 Vermeij FH, Hasan D, Vermeulen M, Tanghe HL, van Gijn J. Predictive factors for deterioration from hydrocephalus after subarachnoid hemorrhage. Neurology 1994; 44: 1851-1855
  • 44 Yoshioka H, Inagawa T, Tokuda Y, Inokuchi F. Chronic hydrocephalus in elderly patients following subarachnoid hemorrhage. Surg Neurol 2000; 53: 119-124 , discussion 124–125
  • 45 Gruber A, Reinprecht A, Bavinzski G, Czech T, Richling B. Chronic shunt-dependent hydrocephalus after early surgical and early endovascular treatment of ruptured intracranial aneurysms. Neurosurgery 1999; 44: 503-509 , discussion 509–512
  • 46 Gruber A, Ungersböck K, Reinprecht A , et al. Evaluation of cerebral vasospasm after early surgical and endovascular treatment of ruptured intracranial aneurysms. Neurosurgery 1998; 42: 258-267 , discussion 267–268
  • 47 Tietz NW. Clinical Chemistry. 2nd ed. London: WB Saunders; 1994
  • 48 Hirashima Y, Hamada H, Hayashi N, Kuwayama N, Origasa H, Endo S. Independent predictors of late hydrocephalus in patients with aneurysmal subarachnoid hemorrhage—analysis by multivariate logistic regression model. Cerebrovasc Dis 2003; 16: 205-210
  • 49 Douglas MR, Daniel M, Lagord C , et al. High CSF transforming growth factor beta levels after subarachnoid haemorrhage: association with chronic communicating hydrocephalus. J Neurol Neurosurg Psychiatry 2009; 80: 545-550
  • 50 Kastin AJ, Akerstrom V, Pan W. Circulating TGF-beta1 does not cross the intact blood-brain barrier. J Mol Neurosci 2003; 21: 43-48
  • 51 Csuka E, Morganti-Kossmann MC, Lenzlinger PM, Joller H, Trentz O, Kossmann T. IL-10 levels in cerebrospinal fluid and serum of patients with severe traumatic brain injury: relationship to IL-6, TNF-alpha, TGF-beta1 and blood-brain barrier function. J Neuroimmunol 1999; 101: 211-221
  • 52 Morganti-Kossmann MC, Hans VH, Lenzlinger PM , et al. TGF-beta is elevated in the CSF of patients with severe traumatic brain injuries and parallels blood-brain barrier function. J Neurotrauma 1999; 16: 617-628