• Ana Mihajlovska Rendevska Institute of Radiology, Faculty of Medicine “Ss. Cyril and Methodius University”, Skopje, R of North Macedonia
  • Boris Aleksovski Faculty of Natural Sciences and Mathematics,Institute of Biology, Ss. Cyril and Methodius University, R of North Macedonia
  • Blagoj Shuntov University Clinic for Neurosurgery, Faculty of Medicine “Ss. Cyril and Methodius University”, Skopje, R of North Macedonia
  • Vasko Aleksovski University Clinic for Neurology, Faculty of Medicine “Ss. Cyril and Methodius University”, Skopje, R of North Macedonia
  • Mirko Mishel Mircevski University Clinic for Neurosurgery, Faculty of Medicine “Ss. Cyril and Methodius University”, Skopje, R of North Macedonia
  • Viktor Stoev University Clinic for Neurosurgery, Faculty of Medicine “Ss. Cyril and Methodius University”, Skopje, R of North Macedonia
  • Vladimir Rendevski University Clinic for Neurosurgery, Faculty of Medicine “Ss. Cyril and Methodius University”, Skopje, R of North Macedonia


 The worst neurological deterioration after hemorrhagic cerebrovascular insult (H-CVI) occurs due to the formation of perihematomal edema, a proven significant risk factor for poor prognosis. During the last several years, a vast number of studies have focused on the pathogenesis of the brain edema.The main objective of this review paper was the evaluation of the biochemical and molecular mechanisms involved in the pathogenesis of the edema, with a special focus on the inflammatory and oxidative mechanisms. We believe that this brief review could serve as a motivational boost for designing a comprehensive clinical study, in which the radiological and clinical variables, as well as the proinflammatory mediators and the oxidative stress markers will be simultaneously evaluated for their predictive roles in the formation of brain edema.

 Key words:hemorrhagic cerebrovascular insult, perifocal edema, pathogenesis, proinflammatory mediators, oxidative stress.


1.Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet 2009;373:1632–44.
2.Van Asch CJ, Luitse MJ, Rinkel GJ, 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 2010;9(2):167–76.
3.Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H. Spontaneous intracerebral hemorrhage. N Engl J Med 2001;344(19):1450–60.
4.Zia E, Hedblad B, Pessah-Rasmussen H, et al. Blood pressure in relation to the incidence of cerebral infarction and intracerebral hemorrhage - hypertensive hemorrhage: debated nomenclature is still relevant. Stroke 2007; 38(10):2681–5.
5.Martini SR, Flaherty ML, Brown WM, et al. Risk factors for intracerebral hemorrhage differ according to hemorrhage location. Neurology 2012;79(23):2275–82.
6.Jackson CA, Sudlow CLM. Is hypertension a more frequent risk factor for deep than for lobar supratentorial intracerebral haemorrhage? J Neurol Neurosurg Psychiatry 2006; 77(11):1244–52.
7.Ariesen MJ, Claus SP, Rinkel GJE, Algra A. Risk factors for intracerebral hemorrhage in the general population: A systematic review. Stroke 2003; 34(8):2060–5.
8.Gronbaek H, Johnsen SP, Jepsen P, et al. Liver cirrhosis, other liver diseases, and risk of hospitalisation for intracerebral haemorrhage: a Danish population-based case-control study. BMC Gastroenterol 2008; 8:16.
9.He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials. JAMA1998;280(22):1930–5.
10.Gebel JM Jr, Jauch EC, Brott TG, et al. Relative edema volume is a predictor of outcome in patients with hyperacute spontaneous intracerebral hemorrhage. Stroke. 2002;33(11):2636-41.
11.Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol 2006; 5(1):53–63.
12.Staykov D, Wagner I, Volbers B, et al. Natural course of perihemorrhagic edema after intracerebral hemorrhage. Stroke 2011;42(9):2625–9.
13.Inaji M, Tomita H, Tone O, et al. Chronological changes of perihematomal edema of human intracerebral hematoma. Acta Neurochir Suppl 2003;86:445–8.
14.Venkatasubramanian C, Mlynash M, Finley-Caulfield A, et al. Natural history of perihematomal edema after intracerebral hemorrhage measured by serial magnetic resonance imaging. Stroke 2011;42(1):73–80.
15.Wagner KR, Xi G, Hua Y, et al. Lobar intracerebral hemorrhage model in pigs: rapid edema development in perihematomal white matter. Stroke. 1996;27(3):490-7.
16.Ziai WC. Hematology and inflammatory signaling of intracerebral hemorrhage. Stroke 2013;44(6 Suppl 1):S74–S78
17.Ziai WC. Hematology and inflammatory signaling of intracerebral hemorrhage. Stroke. 2013;44(6 Suppl 1):S74-S78.
18.Xi G, Keep RF, Hua Y, Xiang J, Hoff JT. Attenuation of thrombin-induced brain edema by cerebral thrombin preconditioning. Stroke 1999;30(6):1247–55.
19.Xi GH, Keep RF, Hoff JT. Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats. J Neurosurg 1998;89(6):991–6.
20.Xi G, Wagner KR, Keep RF, et al. Role of blood clot formation on early edema development after experimental intracerebral hemorrhage. Stroke 1998;29(12):2580–6.
21.Li N, Worthmann H, Heeren M, et al. Temporal pattern of cytotoxic edema in the perihematomal region after intracerebral hemorrhage: a serial magnetic resonance imaging study. Stroke 2013;44(4):1144–6.
22.Brunswick AS, Hwang BY, Appelboom G, Hwang RY, Piazza MA, Connolly ES Jr. Serum biomarkers of spontaneous intracerebral hemorrhage induced secondary brain injury. J Neurol Sci. 2012;321(1-2):1-10.
23.Sarker KP, Yamahata H, Nakata M, et al. Recombinant thrombomodulin inhibits thrombin-induced vascular endothelial growth factor production in neuronal cells. Haemostasis. 1999;29(6):343-352.
24.Abilleira S, Montaner J, Molina CA, Monasterio J, Castillo J, Alvarez-Sabín J. Matrix metalloproteinase-9 concentration after spontaneous intracerebral hemorrhage. J Neurosurg. 2003;99(1):65-70.
25.Alvarez-Sabin J, Delgado P, Abilleira S, et al. Temporal profile of matrix metalloproteinases and their inhibitors after spontaneous intracerebral hemorrhage: relationship to clinical and radiological outcome. Stroke 2004;35(6):1316–22.
26.Dziedzic T, Bartus S, Klimkowicz A, Motyl M, Slowik A, Szczudlik A. Intracerebral hemorrhage triggers interleukin-6 and interleukin-10 release in blood. Stroke. 2002;33(9):2334-5.
27.Hammond MD, Taylor RA, Mullen MT, et al. CCR2+ Ly6C(hi) inflammatory monocyte recruitment exacerbates acute disability following intracerebral hemorrhage. J Neurosci. 2014;34(11):3901-9.
28.Castillo J, Davalos A, Alvarez-Sabin J, et al. Molecular signatures of brain injury after intracerebral hemorrhage. Neurology 2002;58(4):624–9.
29.Fang HY, Ko WJ, Lin CY. Plasma interleukin 11 levels correlate with outcome of spontaneous intracerebral hemorrhage. Surg Neurol. 2005;64(6):511-8.
30.Behrouz R. Re-exploring Tumor Necrosis Factor Alpha as a target for therapy in intracerebral hemorrhage. Transl Stroke Res 2016;7(2):93–6.
31.Asakawa H, Miyagawa J, Hanafusa T, Kuwajima M, Matsuzawa Y. High glucose and hyperosmolarity increase secretion of interleukin-1beta in cultured human aortic endothelial cells. J Diabetes Complications 1997;11(3):176–9.
32.Pampfer S, Cordi S, Dutrieux C, Vanderheyden I, Marchand C, De Hertogh R. Interleukin 1beta mediates the effect of high D-glucose on the secretion of TNF-alpha by mouse uterine epithelial cells. Cytokine. 1999;11(7):500-9.
33.Mccoy MK, Tansey MG. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation 2008;5:45.
34.Qureshi AI, Ali Z, Suri MFK, et al. Extracellular glutamate and other amino acids in experimental intracerebral hemorrhage: an in vivo microdialysis study. Crit Care Med 2003;31(5):1482–9.
35.Lees KR. Cerestat and other NMDA antagonists in ischemic stroke. Neurology. 1997;49(5 Suppl 4):S66-S69.
36.Dinkel K, Dhabhar FS, Sapolsky RM. Neurotoxic effects of polymorphonuclear granulocytes on hippocampal primary cultures. Proc Natl Acad Sci U S A. 2004;101(1):331-6.
37.Matz P, Turner C, Weinstein PR, Massa SM, Panter SS, Sharp FR. Heme-oxygenase-1 induction in glia throughout rat brain following experimental subarachnoid hemorrhage. Brain Res. 1996;713(1-2):211-22.
38.Willmore LJ, Rubin JJ. Formation of malonaldehyde and focal brain edema induced by subpial injection of FeCl2 into rat isocortex. Brain Res. 1982;246(1):113–9.
39.Robbins NM, Swanson RA. Opposing effects of glucose on stroke and reperfusion injury: acidosis, oxidative stress, and energy metabolism. Stroke. 2014;45(6):1881-6.
40.Aronowski J, Zhao X. Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke. 2011;42(6):1781-6.
41.Valko M, Morris H, Cronin MT. Metals, toxicity and oxidative stress. Curr Med Chem. 2005;12(10):1161-208.
42.Zhao X, Aronowski J. Nrf2 to pre-condition the brain against injury caused by products of hemolysis after ICH. Transl Stroke Res. 2013;4(1):71-5.
43.Yu YP, Chi XL, Liu LJ. A hypothesis: hydrogen sulfide might be neuroprotective against subarachnoid hemorrhage induced brain injury. ScientificWorldJournal. 2014;2014:432318.
44.Toda N, Ayajiki K, Okamura T. Cerebral blood flow regulation by nitric oxide: recent advances. Pharmacol Rev. 2009;61(1):62-97.
45.Eigel BN, Gursahani H, Hadley RW. ROS are required for rapid reactivation of Na+/Ca2+ exchanger in hypoxic reoxygenated guinea pig ventricular myocytes. Am J Physiol Heart Circ Physiol. 2004;286(3):H955-H963.
46.Li Q, Pogwizd SM, Prabhu SD, Zhou L. Inhibiting Na+/K+ ATPase can impair mitochondrial energetics and induce abnormal Ca2+ cycling and automaticity in guinea pig cardiomyocytes. PLoS One. 2014;9(4):e93928.
47.Chrissobolis S, Miller AA, Drummond GR, Kemp-Harper BK, Sobey CG. Oxidative stress and endothelial dysfunction in cerebrovascular disease. Front Biosci (Landmark Ed). 2011;16:1733-45.
48.Gu Y, Dee CM, Shen J. Interaction of free radicals, matrix metalloproteinases and caveolin-1 impacts blood-brain barrier permeability. Front Biosci (Schol Ed). 2011;3:1216-31.
49.Mracsko E, Veltkamp R. Neuroinflammation after intracerebral hemorrhage. Front Cell Neurosci. 2014;8:388.
50.Khaper N, Bryan S, Dhingra S, et al. Targeting the vicious inflammation-oxidative stress cycle for the management of heart failure. Antioxid Redox Signal. 2010;13(7):1033-49.
51.Hu W, Zhou PH, Rao T, Zhang XB, Wang W, Zhang LJ. Adrenomedullin attenuates interleukin-1β-induced inflammation and apoptosis in rat Leydig cells via inhibition of NF-κB signaling pathway. Exp Cell Res. 2015;339(2):220-30.
52.Katsu M, Niizuma K, Yoshioka H, Okami N, Sakata H, Chan PH. Hemoglobin-induced oxidative stress contributes to matrix metalloproteinase activation and blood-brain barrier dysfunction in vivo. J Cereb Blood Flow Metab. 2010;30(12):1939-50.
53.Zhao X, Wu T, Chang CF, et al. Toxic role of prostaglandin E2 receptor EP1 after intracerebral hemorrhage in mice. Brain Behav Immun. 2015;46:293-310.
How to Cite
RENDEVSKA, Ana Mihajlovska et al. CONTEMPORARY ASPECTS IN THE PATHOGENESIS OF BRAIN EDEMA IN PATIENTS WITH HEMORRHAGIC CEREBROVASCULAR INSULT. Journal of Morphological Sciences, [S.l.], v. 3, n. 1, p. 91-96, july 2020. ISSN 2545-4706. Available at: <>. Date accessed: 21 jan. 2022.