Bleeding propensity of cavernous malformations: impact of tight junction alterations on the occurrence of overt hematoma

Laboratory investigation

Dejan Jakimovski M.D.1,5, Hannah Schneider Ph.D.1,2, Karl Frei M.D., Ph.D.1,2, Lieven N. Kennes Ph.D.4, and Helmut Bertalanffy M.D., Ph.D.1,3
View More View Less
  • 1 Department of Neurosurgery and
  • | 2 Laboratory for Molecular Neurooncology, University Hospital Zurich, Switzerland;
  • | 3 International Neuroscience Institute, Hannover; and
  • | 4 Departments of Medical Statistics and
  • | 5 Neurosurgery, RWTH Aachen University, Aachen, Germany
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $515.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $612.00
Print or Print + Online

Object

Endothelial tight junction (TJ) expression is mostly absent in cerebral cavernous malformations (CMs), which causes increased perilesional erythrocyte and fluid oozing. However, in a subset of CM lesions, foci of preserved TJ staining are observed along endothelial cell contacts. The clinical relevance of this finding is unclear. This study investigates the relevance of the focal TJ protein expression and its association with CM bleeding propensity.

Methods

Immunohistochemical staining for the TJ proteins claudin-5, occludin, and ZO-1 was performed on 32 CM specimens that were resected during 2008–2010. The patients were allocated to 2 groups according to TJ protein expression, and the clinical and radiological parameters of aggressiveness were analyzed and compared.

Results

Complete absence of TJ expression was identified in 20 specimens, and focal TJ protein expression in 12. CMs without TJ immunoreactivity were significantly larger (p = 0.022) and had a significantly greater propensity for development of frank hematomas (p = 0.028) and perilesional edema (p = 0.013). Symptom severity, multiplicity, developmental venous anomaly (DVA) presence, and CM location did not show a significant difference depending on TJ expression.

Conclusions

In a univariate analysis the authors observed significantly less propensity for frank hematomas and perilesional edema as well as smaller size in CM lesions with focal TJ expression compared with CMs without TJ expression. The observed difference in TJ protein expression might be the reason for differences in bleeding propensity of the CM lesions. Although this finding cannot be used in predictive manner at this time, it is a basis for further multivariate analyses of possible CM biological predictors.

Abbreviations used in this paper:

CM = cavernous malformation; DVA = developmental venous anomaly; GLUT-1 = glucose transporter 1; PBS = phosphate-buffered saline; TJ = tight junction.

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $515.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $612.00
  • 1

    Abdulrauf SI, , Kaynar MY, & Awad IA: A comparison of the clinical profile of cavernous malformations with and without associated venous malformations. Neurosurgery 44:4147, 1999

    • Search Google Scholar
    • Export Citation
  • 2

    Aiba T, , Tanaka R, , Koike T, , Kameyama S, , Takeda N, & Komata T: Natural history of intracranial cavernous malformations. J Neurosurg 83:5659, 1995

    • Search Google Scholar
    • Export Citation
  • 3

    Al-Holou WN, , O'Lynnger TM, , Pandey AS, , Gemmete JJ, , Thompson BG, & Muraszko KM, et al.: Natural history and imaging prevalence of cavernous malformations in children and young adults. Clinical article. J Neurosurg Pediatr 9:198205, 2012

    • Search Google Scholar
    • Export Citation
  • 4

    Al-Shahi Salman R, , Hall JM, , Horne MA, , Moultrie F, , Josephson CB, & Bhattacharya JJ, et al.: Untreated clinical course of cerebral cavernous malformations: a prospective, population-based cohort study. Lancet Neurol 11:217224, 2012

    • Search Google Scholar
    • Export Citation
  • 5

    Awad IA, , Robinson JR Jr, , Mohanty S, & Estes ML: Mixed vascular malformations of the brain: clinical and pathogenetic considerations. Neurosurgery 33:179188, 1993

    • Search Google Scholar
    • Export Citation
  • 6

    Barker FG II, , Amin-Hanjani S, , Butler WE, , Lyons S, , Ojemann RG, & Chapman PH, et al.: Temporal clustering of hemorrhages from untreated cavernous malformations of the central nervous system. Neurosurgery 49:1525, 2001

    • Search Google Scholar
    • Export Citation
  • 7

    Bertalanffy H, , Benes L, , Miyazawa T, , Alberti O, , Siegel AM, & Sure U: Cerebral cavernomas in the adult. Review of the literature and analysis of 72 surgically treated patients. Neurosurg Rev 25:155, 2002

    • Search Google Scholar
    • Export Citation
  • 8

    Burkhardt JK, , Schmidt D, , Schoenauer R, , Brokopp C, , Agarkova I, & Bozinov O, et al.: Upregulation of transmembrane endothelial junction proteins in human cerebral cavernous malformations. Neurosurg Focus 29:3 E3, 2010

    • Search Google Scholar
    • Export Citation
  • 9

    Clatterbuck RE, , Eberhart CG, , Crain BJ, & Rigamonti D: Ultrastructural and immunocytochemical evidence that an incompetent blood-brain barrier is related to the pathophysiology of cavernous malformations. J Neurol Neurosurg Psychiatry 71:188192, 2001

    • Search Google Scholar
    • Export Citation
  • 10

    Dobrogowska DH, & Vorbrodt AW: Quantitative immunocytochemical study of blood-brain barrier glucose transporter (GLUT-1) in four regions of mouse brain. J Histochem Cytochem 47:10211030, 1999

    • Search Google Scholar
    • Export Citation
  • 11

    Fanning AS, , Jameson BJ, , Jesaitis LA, & Anderson JM: The tight junction protein ZO-1 establishes a link between the trans-membrane protein occludin and the actin cytoskeleton. J Biol Chem 273:2974529753, 1998

    • Search Google Scholar
    • Export Citation
  • 12

    Furuse M: Molecular basis of the core structure of tight junctions. Cold Spring Harb Perspect Biol 2:a002907, 2010

  • 13

    Gerhart DZ, , LeVasseur RJ, , Broderius MA, & Drewes LR: Glucose transporter localization in brain using light and electron immunocytochemistry. J Neurosci Res 22:464472, 1989

    • Search Google Scholar
    • Export Citation
  • 14

    Glading A, , Han J, , Stockton RA, & Ginsberg MH: KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell–cell junctions. J Cell Biol 179:247254, 2007

    • Search Google Scholar
    • Export Citation
  • 15

    Gross BA, , Lin N, , Du R, & Day AL: The natural history of intracranial cavernous malformations. Neurosurg Focus 30:6 E24, 2011

  • 16

    Kim DS, , Park YG, , Choi JU, , Chung SS, & Lee KC: An analysis of the natural history of cavernous malformations. Surg Neurol 48:918, 1997

  • 17

    Kivelev J, , Laakso A, , Niemelä M, & Hernesniemi J: A proposed grading system of brain and spinal cavernomas. Neurosurgery 69:807814, 2011

    • Search Google Scholar
    • Export Citation
  • 18

    Kondziolka D, , Lunsford LD, & Kestle JR: The natural history of cerebral cavernous malformations. J Neurosurg 83:820824, 1995

  • 19

    Lippoldt A, , Kniesel U, , Liebner S, , Kalbacher H, , Kirsch T, & Wolburg H, et al.: Structural alterations of tight junctions are associated with loss of polarity in stroke-prone spontaneously hypertensive rat blood-brain barrier endothelial cells. Brain Res 885:251261, 2000

    • Search Google Scholar
    • Export Citation
  • 20

    Mathiesen T, , Edner G, & Kihlström L: Deep and brainstem cavernomas: a consecutive 8-year series. J Neurosurg 99:3137, 2003

  • 21

    Moriarity JL, , Wetzel M, , Clatterbuck RE, , Javedan S, , Sheppard JM, & Hoenig-Rigamonti K, et al.: The natural history of cavernous malformations: a prospective study of 68 patients. Neurosurgery 44:11661173, 1999

    • Search Google Scholar
    • Export Citation
  • 22

    Porter PJ, , Willinsky RA, , Harper W, & Wallace MC: Cerebral cavernous malformations: natural history and prognosis after clinical deterioration with or without hemorrhage. J Neurosurg 87:190197, 1997

    • Search Google Scholar
    • Export Citation
  • 23

    Porter RW, , Detwiler PW, , Spetzler RF, , Lawton MT, , Baskin JJ, & Derksen PT, et al.: Cavernous malformations of the brainstem: experience with 100 patients. J Neurosurg 90:5058, 1999

    • Search Google Scholar
    • Export Citation
  • 24

    Pozzati E, , Acciarri N, , Tognetti F, , Marliani F, & Giangaspero F: Growth, subsequent bleeding, and de novo appearance of cerebral cavernous angiomas. Neurosurgery 38:662670, 1996

    • Search Google Scholar
    • Export Citation
  • 25

    Robinson JR, , Awad IA, & Little JR: Natural history of the cavernous angioma. J Neurosurg 75:709714, 1991

  • 26

    Schneider H, , Errede M, , Ulrich NH, , Virgintino D, , Frei K, & Bertalanffy H: Impairment of tight junctions and glucose transport in endothelial cells of human cerebral cavernous malformations. J Neuropathol Exp Neurol 70:417429, 2011

    • Search Google Scholar
    • Export Citation
  • 27

    Stockton RA, , Shenkar R, , Awad IA, & Ginsberg MH: Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity. J Exp Med 207:881896, 2010

    • Search Google Scholar
    • Export Citation
  • 28

    Tu J, , Stoodley MA, , Morgan MK, & Storer KP: Ultrastructural characteristics of hemorrhagic, nonhemorrhagic, and recurrent cavernous malformations. J Neurosurg 103:903909, 2005

    • Search Google Scholar
    • Export Citation
  • 29

    Vaquero J, , Leunda G, , Martínez R, & Bravo G: Cavernomas of the brain. Neurosurgery 12:208210, 1983

  • 30

    Wang CC, , Liu A, , Zhang JT, , Sun B, & Zhao YL: Surgical management of brain-stem cavernous malformations: report of 137 cases. Surg Neurol 59:444454, 2003

    • Search Google Scholar
    • Export Citation
  • 31

    Wong JH, , Awad IA, & Kim JH: Ultrastructural pathological features of cerebrovascular malformations: a preliminary report. Neurosurgery 46:14541459, 2000

    • Search Google Scholar
    • Export Citation
  • 32

    Wurm G, , Schnizer M, & Fellner FA: Cerebral cavernous malformations associated with venous anomalies: surgical considerations. Neurosurgery 57:1 Suppl 4258, 2005

    • Search Google Scholar
    • Export Citation
  • 33

    Zabramski JM, , Wascher TM, , Spetzler RF, , Johnson B, , Golfinos J, & Drayer BP, et al.: The natural history of familial cavernous malformations: results of an ongoing study. J Neurosurg 80:422432, 1994

    • Search Google Scholar
    • Export Citation
  • 34

    Zhao Y, , Tan YZ, , Zhou LF, , Wang HJ, & Mao Y: Morphological observation and in vitro angiogenesis assay of endothelial cells isolated from human cerebral cavernous malformations. Stroke 38:13131319, 2007

    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 199 91 4
Full Text Views 348 18 0
PDF Downloads 186 9 0
EPUB Downloads 0 0 0