Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Targeting secondary injury in intracerebral haemorrhage—perihaematomal oedema

Nature Reviews Neurology volume 11, pages 111–122 (2015)Cite this article

Subjects

Key Points

  • Secondary injury following intracerebral haemorrhage (ICH) is caused by perihaemorrhagic inflammation, toxic products of blood breakdown, and perihaematomal oedema (PHO)

  • Secondary injury contributes to neurological deterioration over an extended period of hours to days and, therefore, offers a long therapeutic window

  • PHO forms in three stages in accordance with Starling's principle: stage 1 is characterized by ionic oedema, and stages 2 and 3 by progressive vasogenic oedema

  • PHO is a pathophysiological marker of secondary injury that could provide a useful surrogate end point for testing novel neuroprotective agents

  • PHO might also be clinically relevant, as it augments the mass effect of haemorrhage; further studies could identify subgroups of patients who would benefit from therapies that ameliorate PHO

  • Combination treatment regimens that target different stages of PHO formation might be most effective to reduce swelling

Abstract

Perihaematomal oedema (PHO) is an important pathophysiological marker of secondary injury in intracerebral haemorrhage (ICH). In this Review, we describe a novel method to conceptualize PHO formation within the framework of Starling's principle of movement of fluid across a capillary wall. We consider progression of PHO through three stages, characterized by ionic oedema (stage 1) and progressive vasogenic oedema (stages 2 and 3). In this context, possible modifiers of PHO volume and their value in identifying patients who would benefit from therapies that target secondary injury are discussed; the practicalities of using neuroimaging to measure PHO volume are also considered. We examine whether PHO can be used as a predictor of neurological outcome following ICH, and we provide an overview of emerging therapies. Our discussion emphasizes that PHO has clinical relevance both as a therapeutic target, owing to its augmentation of the mass effect of a haemorrhage, and as a surrogate marker for novel interventions that target secondary injury.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A modification of Starling's equation that includes separate filtration coefficients for the hydrostatic and osmotic forces.
Figure 2: Hypothetical model of NKCC1 and SUR1–TRPM4 involvement in PHO.
Figure 3: Expression of SUR1–TRPM4 in perihaematomal tissues following primary spontaneous ICH.
Figure 4: Intracerebral haemorrhage and PHO as seen in a CT scan performed at hospital admission.

Similar content being viewed by others

References

  1. van Asch, C. J. et al. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 9, 167–176 (2010).

    Article  PubMed  Google Scholar 

  2. Keep, R. F., Hua, Y. & Xi, G. H. Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol. 11, 720–731 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Brouwers, H. B. & Greenberg, S. M. Hematoma expansion following acute intracerebral hemorrhage. Cerebrovasc. Dis. 35, 195–201 (2013).

    Article  PubMed  Google Scholar 

  4. Li, N. et al. Association of molecular markers with perihematomal edema and clinical outcome in intracerebral hemorrhage. Stroke 44, 658–663 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Wang, J. & Tsirka, S. E. Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage. Brain 128, 1622–1633 (2005).

    Article  PubMed  Google Scholar 

  6. Li, G. et al. Neuroprotective effects of argatroban and C5a receptor antagonist (PMX53) following intracerebral haemorrhage. Clin. Exp. Immunol. 175, 285–295 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Appelboom, G. et al. Volume-dependent effect of perihaematomal oedema on outcome for spontaneous intracerebral haemorrhages. J. Neurol. Neurosurg. Psychiatry 84, 488–493 (2013).

    Article  PubMed  Google Scholar 

  8. Arima, H. et al. Significance of perihematomal edema in acute intracerebral hemorrhage: the INTERACT trial. Neurology 73, 1963–1968 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Xi, G. H., Keep, R. F. & Hoff, J. T. Pathophysiology of brain edema formation. Neurosurg. Clin. N. Am. 13, 371–383 (2002).

    Article  PubMed  Google Scholar 

  10. Simard, J. M., Kent, T. A., Chen, M. K., Tarasov, K. V. & Gerzanich, V. Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol. 6, 258–268 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kahle, K. T. et al. Molecular mechanisms of ischemic cerebral edema: role of electroneutral ion transport. Physiology (Bethesda) 24, 257–265 (2009).

    CAS  Google Scholar 

  12. Venkatasubramanian, C. et al. Natural history of perihematomal edema after intracerebral hemorrhage measured by serial magnetic resonance imaging. Stroke 42, 73–80 (2011).

    Article  PubMed  Google Scholar 

  13. Inaji, M. et al. Chronological changes of perihematomal edema of human intracerebral hematoma. Acta Neurochir. Suppl. 86, 445–448 (2003).

    CAS  PubMed  Google Scholar 

  14. Suga, S., Sato, S., Yunoki, K. & Mihara, B. Sequential change of brain edema by semiquantitative measurement on MRI in patients with hypertensive intracerebral hemorrhage. Acta Neurochir. Suppl. (Wien) 60, 564–567 (1994).

    CAS  Google Scholar 

  15. Wagner, K. R. et al. Lobar intracerebral hemorrhage model in pigs—rapid edema development in perihematomal white matter. Stroke 27, 490–497 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Brunswick, A. S. et al. Serum biomarkers of spontaneous intracerebral hemorrhage induced secondary brain injury. J. Neurol. Sci. 321, 1–10 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. MacAulay, N., Hamann, S. & Zeuthen, T. Water transport in the brain: role of cotransporters. Neuroscience 129, 1031–1044 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Pohl, P. Combined transport of water and ions through membrane channels. Biol. Chem. 385, 921–926 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Hoomann, T., Jahnke, N., Horner, A., Keller, S. & Pohl, P. Filter gate closure inhibits ion but not water transport through potassium channels. Proc. Natl Acad. Sci. USA 110, 10842–10847 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lippoldt, A. et al. Organization of choroid plexus epithelial and endothelial cell tight junctions and regulation of claudin-1, -2 and -5 expression by protein kinase C. Neuroreport 11, 1427–1431 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Xu, J. et al. Internalization of aquaporin-4 after collagenase-induced intracerebral hemorrhage. Anat. Rec. http://dx.doi.org/10.1002/ar.23055

  22. Stokum, J. A., Kurland, D. B., Gerzanich, V. & Simard, J. M. Mechanisms of astrocyte-mediated cerebral edema. Neurochem. Res. http://dx.doi.org/10.1007/s11064-014-1374-3.

  23. Simard, J. M., Kahle, K. T. & Gerzanich, V. Molecular mechanisms of microvascular failure in central nervous system injury—synergistic roles of NKCC1 and SUR1/TRPM4. J. Neurosurg. 113, 622–629 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dziedzic, T. et al. Intracerebral hemorrhage triggers interleukin-6 and interleukin-10 release in blood. Stroke 33, 2334–2335 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Qureshi, A. I. et al. Extracellular glutamate and other amino acids in experimental intracerebral hemorrhage: an in vivo microdialysis study. Crit. Care Med. 31, 1482–1489 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Simard, J. M. et al. Glibenclamide reduces inflammation, vasogenic edema, and caspase-3 activation after subarachnoid hemorrhage. J. Cereb. Blood Flow Metab. 29, 317–330 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Tosun, C. et al. Inhibition of the Sur1–Trpm4 channel reduces neuroinflammation and cognitive impairment in subarachnoid hemorrhage. Stroke 44, 3522–3528 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Simard, J. M., Woo, S. K., Bhatta, S. & Gerzanich, V. Drugs acting on SUR1 to treat CNS ischemia and trauma. Curr. Opin. Pharmacol. 8, 42–49 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Aronowski, J. & Zhao, X. Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke 42, 1781–1786 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Wang, J. Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog. Neurobiol. 92, 463–477 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhao, X. R. et al. Distinct patterns of intracerebral hemorrhage-induced alterations in NF-κB subunit, iNOS, and COX-2 expression. J. Neurochem. 101, 652–663 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Sansing, L. H. et al. Toll-like receptor 4 contributes to poor outcome after intracerebral hemorrhage. Ann. Neurol. 70, 646–656 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bodmer, D., Vaughan, K. A., Zacharia, B. E., Hickman, Z. L. & Connolly, E. S. The molecular mechanisms that promote edema after intracerebral hemorrhage. Transl. Stroke Res. 3 (Suppl. 1), 52–61 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Wang, Y. C. et al. Toll-like receptor 2/4 heterodimer mediates inflammatory injury in intracerebral hemorrhage. Ann. Neurol. 75, 876–889 (2014).

    Article  CAS  PubMed  Google Scholar 

  35. Suo, Z., Wu, M., Citron, B. A., Gao, C. & Festoff, B. W. Persistent protease-activated receptor 4 signaling mediates thrombin-induced microglial activation. J. Biol. Chem. 278, 31177–31183 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Lei, B. et al. Tumor necrosis factor alpha antagonism improves neurological recovery in murine intracerebral hemorrhage. J. Neuroinflammation 10, 103 (2013).

    PubMed  PubMed Central  Google Scholar 

  37. Masada, T. et al. Attenuation of intracerebral hemorrhage and thrombin-induced brain edema by overexpression of interleukin-1 receptor antagonist. J. Neurosurg. 95, 680–686 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Megyeri, P. et al. Recombinant human tumor necrosis factor alpha constricts pial arterioles and increases blood–brain barrier permeability in newborn piglets. Neurosci. Lett. 148, 137–140 (1992).

    Article  CAS  PubMed  Google Scholar 

  39. Aslam, M., Ahmad, N., Srivastava, R. & Hemmer, B. TNF-alpha induced NFκB signaling and p65 (RelA) overexpression repress Cldn5 promoter in mouse brain endothelial cells. Cytokine 57, 269–275 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Bartha, K., Dömötör, E., Lanza, F., Adam-Vizi, V. & Machovich, R. Identification of thrombin receptors in rat brain capillary endothelial cells. J. Cereb. Blood Flow Metab. 20, 175–182 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Zheng, G. Q. et al. Long-time course of protease-activated receptor-1 expression after intracerebral hemorrhage in rats. Neurosci. Lett. 459, 62–65 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Zhou, Z. H., Qu, F. & Zhang, C. D. Systemic administration of argatroban inhibits protease-activated receptor-1 expression in perihematomal tissue in rats with intracerebral hemorrhage. Brain Res. Bull. 86, 235–238 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Satpathy, M., Gallagher, P., Lizotte-Waniewski, M. & Srinivas, S. P. Thrombin-induced phosphorylation of the regulatory light chain of myosin II in cultured bovine corneal endothelial cells. Exp. Eye Res. 79, 477–486 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Bijli, K. M. et al. c-Src interacts with and phosphorylates RelA/p65 to promote thrombin-induced ICAM-1 expression in endothelial cells. Am. J. Physiol. Lung Cell Mol. Physiol. 292, L396–L404 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Mracsko, E. et al. Leukocyte invasion of the brain after experimental intracerebral hemorrhage in mice. Stroke 45, 2107–2114 (2014).

    Article  PubMed  Google Scholar 

  46. Rolland, W. B. et al. Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage. Exp. Neurol. 241, 45–55 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Xi, G. H., Keep, R. F. & Hoff, J. T. Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats. J. Neurosurg. 89, 991–996 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Lee, K. R. et al. Edema from intracerebral hemorrhage: the role of thrombin. J. Neurosurg. 84, 91–96 (1996).

    Article  CAS  PubMed  Google Scholar 

  49. Sun, Z. et al. Recombinant hirudin treatment modulates aquaporin-4 and aquaporin-9 expression after intracerebral hemorrhage in vivo. Mol. Biol. Rep. 36, 1119–1127 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Gebel, J. M. et al. Decreased perihematomal edema in thrombolysis-related intracerebral hemorrhage compared with spontaneous intracerebral hemorrhage. Stroke 31, 596–600 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Levine, J. M. et al. Early edema in warfarin-related intracerebral hemorrhage. Neurocrit. Care 7, 58–63 (2007).

    Article  PubMed  Google Scholar 

  52. Ducruet, A. F. et al. The complement cascade as a therapeutic target in intracerebral hemorrhage. Exp. Neurol. 219, 398–403 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hua, Y., Xi, G., Keep, R. F. & Hoff, J. T. Complement activation in the brain after experimental intracerebral hemorrhage. J. Neurosurg. 92, 1016–1022 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Garrett, M. C. et al. Synergistic neuroprotective effects of C3a and C5a receptor blockade following intracerebral hemorrhage. Brain Res. 1298, 171–177 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Huang, F. P. et al. Brain edema after experimental intracerebral hemorrhage: role of hemoglobin degradation products. J. Neurosurg. 96, 287–293 (2002).

    Article  PubMed  Google Scholar 

  56. Nakamura, T. et al. Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage. J. Neurosurg. 100, 672–678 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Xie, Q. et al. Deferoxamine attenuates white matter injury in a piglet intracerebral hemorrhage model. Stroke 45, 290–292 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Lou, M., Lieb, K. & Selim, M. The relationship between hematoma iron content and perihematoma edema: an MRI study. Cerebrovasc. Dis. 27, 266–271 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wagner, I. et al. Radiopacity of intracerebral hemorrhage correlates with perihemorrhagic edema. Eur. J. Neurol. 19, 525–528 (2012).

    Article  CAS  PubMed  Google Scholar 

  60. Katsu, M. et al. Hemoglobin-induced oxidative stress contributes to matrix metalloproteinase activation and blood–brain barrier dysfunction in vivo. J. Cereb. Blood Flow Metab. 30, 1939–1950 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Florczak-Rzepka, M., Grond-Ginsbach, C., Montaner, J. & Steiner, T. Matrix metalloproteinases in human spontaneous intracerebral hemorrhage: an update. Cerebrovasc. Dis. 34, 249–262 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Zhou, H. J. et al. Thrombin-triggered angiogenesis in rat brains following experimental intracerebral hemorrhage. J. Neurosurg. 117, 920–928 (2012).

    Article  CAS  PubMed  Google Scholar 

  63. Liu, D. Z. et al. Blood–brain barrier breakdown and repair by Src after thrombin-induced injury. Ann. Neurol. 67, 526–533 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Gebel, J. M. Jr et al. Natural history of perihematomal edema in patients with hyperacute spontaneous intracerebral hemorrhage. Stroke 33, 2631–2635 (2002).

    Article  PubMed  Google Scholar 

  65. Mould, W. A. et al. Minimally invasive surgery plus recombinant tissue-type plasminogen activator for intracerebral hemorrhage evacuation decreases perihematomal edema. Stroke 44, 627–634 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. McCarron, M. O., McCarron, P. & Alberts, M. J. Location characteristics of early perihaematomal oedema. J. Neurol. Neurosurg. Psychiatry 77, 378–380 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wagner, I. et al. Sex differences in perihemorrhagic edema evolution after spontaneous intracerebral hemorrhage. Eur. J. Neurol. 19, 1477–1481 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Gu, Y., Xi, G., Liu, W., Keep, R. F. & Hua, Y. Estrogen reduces iron-mediated brain edema and neuronal death. Acta Neurochir. Suppl. 106, 159–162 (2010).

    Article  CAS  PubMed  Google Scholar 

  69. Sykora, M., Diedler, J., Turcani, P., Rupp, A. & Steiner, T. Subacute perihematomal edema in intracerebral hemorrhage is associated with impaired blood pressure regulation. J. Neurol. Sci. 284, 108–112 (2009).

    Article  PubMed  Google Scholar 

  70. James, M. L., Blessing, R., Bennett, E. & Laskowitz, D. T. Apolipoprotein E modifies neurological outcome by affecting cerebral edema but not hematoma size after intracerebral hemorrhage in humans. J. Stroke Cerebrovasc. Dis. 18, 144–149 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  71. McCarron, M. O. et al. Intracerebral hemorrhage outcome: apolipoprotein E genotype, hematoma, and edema volumes. Neurology 53, 2176–2179 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. Biffi, A. et al. Variants at APOE influence risk of deep and lobar intracerebral hemorrhage. Ann. Neurol. 68, 934–943 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Qureshi, A. I. et al. Effect of systolic blood pressure reduction on hematoma expansion, perihematomal edema, and 3-month outcome among patients with intracerebral hemorrhage: results from the antihypertensive treatment of acute cerebral hemorrhage study. Arch. Neurol. 67, 570–576 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Vemmos, K. N. et al. Association between 24-h blood pressure monitoring variables and brain oedema in patients with hyperacute stroke. J. Hypertens. 21, 2167–2173 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Sansing, L. H., Messe, S. R., Cucchiara, B. L., Lyden, P. D. & Kasner, S. E. Anti-adrenergic medications and edema development after intracerebral hemorrhage. Neurocrit. Care 14, 395–400 (2011).

    Article  CAS  PubMed  Google Scholar 

  76. Mayer, S. A. et al. Perilesional blood flow and edema formation in acute intracerebral hemorrhage: a SPECT study. Stroke 29, 1791–1798 (1998).

    Article  CAS  PubMed  Google Scholar 

  77. Deegan, B. M. et al. Elderly women regulate brain blood flow better than men do. Stroke 42, 1988–1993 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Naval, N. S. et al. An association of prior statin use with decreased perihematomal edema. Neurocrit. Care 8, 13–18 (2008).

    Article  PubMed  Google Scholar 

  79. Qureshi, A. I. et al. Association of serum glucose concentrations during acute hospitalization with hematoma expansion, perihematomal edema, and three month outcome among patients with intracerebral hemorrhage. Neurocrit. Care 15, 428–435 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Allen, C. L. & Bayraktutan, U. Antioxidants attenuate hyperglycaemia-mediated brain endothelial cell dysfunction and blood–brain barrier hyperpermeability. Diabetes Obes. Metab. 11, 480–490 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Song, E. C. et al. Hyperglycemia exacerbates brain edema and perihematomal cell death after intracerebral hemorrhage. Stroke 34, 2215–2220 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Feng, W., Tauhid, S., Goel, S., Sidorov, E. V. & Selim, M. Hyperglycemia and outcome in intracerebral hemorrhage: from bedside to bench-more study is needed. Transl. Stroke Res. 3 (Suppl. 1), 113–118 (2012).

    Article  PubMed  Google Scholar 

  83. Staykov, D. et al. Mild prolonged hypothermia for large intracerebral hemorrhage. Neurocrit. Care 18, 178–183 (2013).

    Article  PubMed  Google Scholar 

  84. Kawai, N., Kawanishi, M., Okauchi, M. & Nagao, S. Effects of hypothermia on thrombin-induced brain edema formation. Brain Res. 895, 50–58 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Sun, H., Tang, Y., Guan, X., Li, L. & Wang, D. Effects of selective hypothermia on blood–brain barrier integrity and tight junction protein expression levels after intracerebral hemorrhage in rats. Biol. Chem. 394, 1317–1324 (2013).

    Article  CAS  PubMed  Google Scholar 

  86. Wagner, I. et al. Effects of continuous hypertonic saline infusion on perihemorrhagic edema evolution. Stroke 42, 1540–1545 (2011).

    Article  PubMed  Google Scholar 

  87. Ryu, J. H. et al. Induced and sustained hypernatremia for the prevention and treatment of cerebral edema following brain injury. Neurocrit. Care 19, 222–231 (2013).

    Article  CAS  PubMed  Google Scholar 

  88. Sansing, L. H. et al. Edema after intracerebral hemorrhage: correlations with coagulation parameters and treatment. J. Neurosurg. 98, 985–992 (2003).

    Article  PubMed  Google Scholar 

  89. Wang, J. et al. β-adrenoceptor mediated surgery-induced production of pro-inflammatory cytokines in rat microglia cells. J. Neuroimmunol. 223, 77–83 (2010).

    Article  CAS  PubMed  Google Scholar 

  90. Yang, D. et al. Statins protect the blood brain barrier acutely after experimental intracerebral hemorrhage. J. Behav. Brain Sci. 3, 100–106 (2013).

    Article  CAS  PubMed  Google Scholar 

  91. Zazulia, A. R., Diringer, M. N., Derdeyn, C. P. & Powers, W. J. Progression of mass effect after intracerebral hemorrhage. Stroke 30, 1167–1173 (1999).

    Article  CAS  PubMed  Google Scholar 

  92. Walberer, M. et al. Midline-shift corresponds to the amount of brain edema early after hemispheric stroke—an MRI study in rats. J. Neurosurg. Anesthesiol. 19, 105–110 (2007).

    Article  PubMed  Google Scholar 

  93. Zazulia, A. R., Videen, T. O., Diringer, M. N. & Powers, W. J. Poor correlation between perihematomal MRI hyperintensity and brain swelling after intracerebral hemorrhage. Neurocrit. Care 15, 436–441 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Volbers, B. et al. Semi-automatic volumetric assessment of perihemorrhagic edema with computed tomography. Eur. J. Neurol. 18, 1323–1328 (2011).

    Article  PubMed  Google Scholar 

  95. Gebel, J. M. Jr et al. Relative edema volume is a predictor of outcome in patients with hyperacute spontaneous intracerebral hemorrhage. Stroke 33, 2636–2641 (2002).

    Article  PubMed  Google Scholar 

  96. Staykov, D. et al. Natural course of perihemorrhagic edema after intracerebral hemorrhage. Stroke 42, 2625–2629 (2011).

    Article  PubMed  Google Scholar 

  97. Sun, W. et al. Predictors of late neurological deterioration after spontaneous intracerebral hemorrhage. Neurocrit. Care 19, 299–305 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Romero, J. M. et al. Spot sign score predicts rapid bleeding in spontaneous intracerebral hemorrhage. Emerg. Radiol. 19, 195–202 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Lee, S. H. et al. Effects of celecoxib on hematoma and edema volumes in primary intracerebral hemorrhage: a multicenter randomized controlled trial. Eur. J. Neurol. 20, 1161–1169 (2013).

    Article  PubMed  Google Scholar 

  100. Chu, K. et al. Celecoxib induces functional recovery after intracerebral hemorrhage with reduction of brain edema and perihematomal cell death. J. Cereb. Blood Flow Metab. 24, 926–933 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Fu, Y. et al. Fingolimod for the treatment of intracerebral hemorrhage: a 2-arm proof-of-concept study. JAMA Neurol. 71, 1092–1101 (2014).

    Article  PubMed  Google Scholar 

  102. Yeatts, S. D., Palesch, Y. Y., Moy, C. S. & Selim, M. High dose deferoxamine in intracerebral hemorrhage (HI-DEF) trial: rationale, design, and methods. Neurocrit. Care 19, 257–266 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gu, Y., Hua, Y., Keep, R. F., Morgenstern, L. B. & Xi, G. Deferoxamine reduces intracerebral hematoma-induced iron accumulation and neuronal death in piglets. Stroke 40, 2241–2243 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Okauchi, M. et al. Deferoxamine treatment for intracerebral hemorrhage in aged rats: therapeutic time window and optimal duration. Stroke 41, 375–382 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. Gonzales, N. R. et al. Design of a prospective, dose-escalation study evaluating the Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage (SHRINC). Int. J. Stroke 8, 388–396 (2013).

    Article  PubMed  Google Scholar 

  106. Zhao, X. R. et al. Hematoma resolution as a target for intracerebral hemorrhage treatment: role for peroxisome proliferator-activated receptor γ in microglia/macrophages. Ann. Neurol. 61, 352–362 (2007).

    Article  CAS  PubMed  Google Scholar 

  107. Rincon, F., Friedman, D. P., Bell, R., Mayer, S. A. & Bray, P. F. Targeted temperature management after intracerebral hemorrhage (TTM-ICH): methodology of a prospective randomized clinical trial. Int. J. Stroke 9, 646–651 (2014).

    Article  PubMed  Google Scholar 

  108. Kollmar, R. et al. Cooling in intracerebral hemorrhage (CINCH) trial: protocol of a randomized German–Austrian clinical trial. Int. J. Stroke 7, 168–172 (2012).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

S.U. is supported by the Leon Rosenberg, MD Medical Student Research Fund in Genetics (Yale University School of Medicine) and a 2014 Student Scholarship in Cerebrovascular Disease and Stroke (American Heart Association Stroke Council). L.A.B. is supported by the National Institute of Neurological Disorders and Stroke (NINDS; K12-NS049453). J.M.S. is supported by grants from the Department of Veterans Affairs (Baltimore; BX001629), the NINDS (NS060801, NS061808), and the National Heart, Lung and Blood Institute (HL082517).

Author information

Authors and Affiliations

  1. Department of Neurology, Yale University School of Medicine, 333 Cedar Street, New Haven, 06510, CT, USA

    Sebastian Urday, Lauren A. Beslow & Kevin N. Sheth

  2. Department of Pathology, Yale University School of Medicine, 333 Cedar Street, New Haven, 06510, CT, USA

    Alexander O. Vortmeyer

  3. Department of Neurology, Massachusetts General Hospital, 55 Fruit Street, Boston, 02114, MA, USA

    W. Taylor Kimberly & Jonathan Rosand

  4. Department of Neurology, Beth Israel Deaconess Medical Centre, 330 Brookline Avenue, Boston, 02215, MA, USA

    Magdy H. Selim

  5. Department of Neurosurgery, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, 21201-1559, MD, USA

    J. Marc Simard

Authors
  1. Sebastian Urday
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W. Taylor Kimberly
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lauren A. Beslow
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexander O. Vortmeyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Magdy H. Selim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jonathan Rosand
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J. Marc Simard
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kevin N. Sheth
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.U. and K.N.S. originated the overall concept for this Review. All authors contributed to several drafts of the article and provided important intellectual exchanges during formulation of key concepts. S.U., J.M.S. and K.N.S. contributed to every draft and supplied figures. A.O.V. was responsible for procuring autopsy specimens, and J.M.S. was responsible for SUR1 detection in intracerebral haemorrhage tissue shown in Figure 3.

Corresponding author

Correspondence to Kevin N. Sheth.

Ethics declarations

Competing interests

W.T.K., and L.A.B. and K.N.S. are investigators in GAMES-RP, a phase II study of an investigational compound aimed at preventing swelling after large stroke. J.M.S. holds a US patent (7,285,574, Methods for treating neural cell swelling). The other authors declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Urday, S., Kimberly, W., Beslow, L. et al. Targeting secondary injury in intracerebral haemorrhage—perihaematomal oedema. Nat Rev Neurol 11, 111–122 (2015). https://doi.org/10.1038/nrneurol.2014.264

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2014.264

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing