(Stroke. 2006;37:762.)
© 2006 American Heart Association, Inc.
Letters to the Editor |
There Is More to it Than: the Greater the Infarction Volume, the More Probable Is a Malignant MCA Infarction
Max-Planck-Institute for Neurological Research, Cologne, Germany, Department of Neurosurgery, University of Cologne, Germany
Department of Neurology, Dr.-Horst-Schmidt-Hospital, Wiesbaden, Germany, Department of Neurology, Ludwig-Maximilians-University, Munich, Germany
Max-Planck-Institute for Neurological Research, Cologne, Germany
To the Editor:
In Stroke, we read with great interest the original article by Serena et al1 on prediction of malignant middle cerebral artery (MCA) infarction. As a group working experimentally and clinically on malignant MCA infarction,2–4 we would like to comment on their competent study on molecular blood-brain barrier (BBB) disruption markers in patients who developed a malignant MCA infarction, because their work establishes a new point of view in the understanding of this life-threatening disease.
The approach of Serena and colleagues to detect matrix metalloproteinases (MMPs) and basal lamina decomposition products like cellular fibronectin in plasma of patients allows a quite precise prediction of malignant MCA infarction.1 Cerebral ischemia leads to an up-regulation of MMPs, which degrade elements of the extracellular matrix and of the basal lamina.5,6 BBB disruption may result from this process because the basal lamina is part of the blood-brain barrier system. Thus, substances involved in this process are of substantial interest not only for diagnostic purposes but also for investigations of the mechanisms resulting in malignant infarction and associated complications like hemorrhagic transformation.7–9 Recently, studies using various imaging techniques have emphasized that the size of the initial infarct volume3,10,11 and possibly the intensity of blood-flow reduction12 is a good predictor of malignant brain edema formation. We should recognize, however, that in individual cases presented in these studies, a similar size of infarction resulted in completely different clinical courses highlighting the fact that a simple monocausal relationship does not exist for the development of malignant MCA infarction and that inter- or even intraindividual variations need further mechanistic explanations. High levels of MMPs and of related substrates were thought to play a key role for such secondary deterioration,8 and in this respect, the work of Serena and colleagues is a promising step.
For a more comprehensive understanding of the pathophysiology of malignant MCA infarction, however, we think that direct, simultaneous measurements in extracellular fluid, cerebrospinal fluid and plasma are needed. In particular, the analysis of extracellular fluid would provide information about the extracellular matrix as the relevant location where MMPs generate their enzymatic activity. Furthermore, MMP-9 is produced by astrocytes as well as endothelial cells, and both glial and endothelial MMP-9 are thought to be responsible for BBB damage.13,14 Combination with microdialysis might provide the chance to get simultaneous information at the parenchymal and vascular side of the basal lamina.
We need longitudinal information on MMPs and related substrates. It is possible that processes at the parenchymal and at the vascular side of the basal lamina follow different time scales. Thus, the origin of substrate alterations detected in plasma remains unclear. The comparison with alterations in the extracellular fluid detected by cerebral microdialysis4,15 might help here, too. More importantly, longitudinal information on extracellular fluid and plasma concentration would also offer the chance to detect slower courses of malignant transformation in individual patients and thus provide the chance for treatment options like hemicraniectomy in these individuals. In this context, complementary translational research with animal models of malignant stroke would be valuable because we could compare with preischemic baseline levels of relevant substances.
References
- Serena J, Blanco M, Castellanos M, Silva Y, Vivancos J, Moro MA, Leira R, Lizasoain I, Castillo J, Davalos A. The Prediction of Malignant Cerebral Infarction by Molecular Brain Barrier Disruption Markers. Stroke. 2005; 36: 1921–1926.
[Abstract/Free Full Text] - Toyota S, Graf R, Valentino M, Yoshimine T, Heiss WD. Malignant infarction in cats after prolonged middle cerebral artery occlusion: glutamate elevation related to decrease of cerebral perfusion pressure. Stroke. 2002; 33: 1383–1391.
[Abstract/Free Full Text] - Dohmen C, Bosche B, Graf R, Staub F, Kracht L, Sobesky J, Neveling M, Brinker G, Heiss WD. Prediction of malignant course in MCA infarction by PET and microdialysis. Stroke. 2003; 34: 2152–2158.
[Abstract/Free Full Text] - Bosche B, Dohmen C, Graf R, Neveling M, Staub F, Kracht L, Sobesky J, Lehnhardt FG, Heiss WD. Extracellular concentrations of non-transmitter amino acids in peri-infarct tissue of patients predict malignant middle cerebral artery infarction. Stroke. 2003; 34: 2908–2913.
[Abstract/Free Full Text] - Rosenberg GA, Estrada EY, Dencoff JE. Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke. 1998; 29: 2189–2195.
[Abstract/Free Full Text] - Gasche Y, Fujimura M, Morita-Fujimura Y, Copin JC, Kawase M, Massengale J, Chan PH. Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: a possible role in blood-brain barrier dysfunction. J Cereb Blood Flow Metab. 1999; 19: 1020–1028.[CrossRef][Medline] [Order article via Infotrieve]
- Hamann GF, Okada Y, del Zoppo GJ. Hemorrhagic transformation and microvascular integrity during focal cerebral ischemia/reperfusion. J Cereb Blood Flow Metab. 1996; 16: 1373–1378.[CrossRef][Medline] [Order article via Infotrieve]
- Wagner S, Hamann GF. [Experimental microvascular and clotting changes–significance for acute stroke therapy.] Nervenarzt. 2003; 74: 123–132, German.[CrossRef][Medline] [Order article via Infotrieve]
- Castellanos M, Leira R, Serena J, Blanco M, Pedraza S, Castillo J, Davalos A. Plasma cellular-fibronectin concentration predicts hemorrhagic transformation after thrombolytic therapy in acute ischemic stroke. Stroke. 2004; 35: 1671–1676.
[Abstract/Free Full Text] - Oppenheim C, Samson Y, Manai R, Lalam T, Vandamme X, Crozier S, Srour A, Cornu P, Dormont D, Rancurel G, Marsault C. Prediction of malignant middle cerebral artery infarction by diffusion-weighted imaging. Stroke. 2000; 31: 2175–2181.
[Abstract/Free Full Text] - Thomalla GJ, Kucinski T, Schoder V, Fiehler J, Knab R, Zeumer H, Weiller C, Rother J. Prediction of malignant middle cerebral artery infarction by early perfusion- and diffusion-weighted magnetic resonance imaging. Stroke. 2003; 34: 1892–1899.
[Abstract/Free Full Text] - Bosche B, Dohmen C, Graf R, Galldiks N, Sobesky J, Kracht L, Lehnhardt FG, Heiss WD. Malignant brain edema after MCA infarction is determined by the severity of the ischemia within the infarction. J Cereb Blood Flow Metab. 2005; 25: S249.[CrossRef]
- Muir EM, Adcock KH, Morgenstern DA, Clayton R, von Stillfried N, Rhodes K, Ellis C, Fawcett JW, Rogers JH. Matrix metalloproteases and their inhibitors are produced by overlapping populations of activated astrocytes. Brain Res Mol Brain Res. 2002; 100 (1–2): 103–117.[Medline] [Order article via Infotrieve]
- Lee JM, Yin K, Hsin I, Chen S, Fryer JD, Holtzman DM, Hsu CY, Xu J. Matrix metalloproteinase-9 in cerebral-amyloid-angiopathy-related hemorrhage. J Neurol Sci. 2005; 229–230: 249–254.[CrossRef]
- Berger C, Schabitz WR, Georgiadis D, Steiner T, Aschoff A, Schwab S. Effects of hypothermia on excitatory amino acids and metabolism in stroke patients: a microdialysis study. Stroke. 2002; 33: 519–524.
[Abstract/Free Full Text]
Hospital Universitari Doctor Josep Trueta, Department of Neurology, Girona, Spain
Hospital Clínico Universitario, Department of Neurology, Universidad de Santiago de Compostela, Spain
Hospital Germans Tries i Pujol, Department of Neurology, Badalona, Spain
Response:
We are grateful to Drs Bosche, Graf, Dohmen and Hamann for the interest shown in our article. We agree that further studies focusing on both the comparison of molecular markers obtained simultaneously in extracellular brain tissue by microdialysis and peripheral blood samples as well as longitudinally obtained data regarding matrix metalloproteinases (MMPs) and related substrates are needed. We supply some information concerning this second point.
As in the studies cited by the authors, we too found that similar infarct volume resulted in very different clinical courses and so agree that better predictors of malignant MCA (m-MCA) infarction are needed. The analysis of extracellular fluid by microdialysis in experimental studies together with plasma samples would provide additional and useful information in clinical practice, particularly considering that microdialysis is not a suitable technique in clinical practice and could only be conducted in animal models or, possibly, after a hemicraniectomy has been performed with a prior decision, which rather defeats the object. Unfortunately, the study of cerebrospinal fluid before hemicraniectomy is not recommended in patients with massive brain infarction because of the risk of herniation.
We agree too in the need for longitudinal studies of MMPs and related substrates, such as cellular fibronectin (c-Fn), because the application of these results may well increase the precision with which we are able to select patients, particularly in cases of delayed malignant brain infarction. In our study we focused on blood samples taken at admission because this is the most relevant sample in identifying patients at risk of subsequent m-MCA infarction. As commented in our article, the blood samples were part of a prospective register aimed at evaluating serum markers of early and late clinical course in acute ischemic stroke. In this register we take blood samples at admission (mean time from stroke onset to blood sample: 2.85±2.06 hours), 24 hours and 72 hours from stroke onset. In the Figure it is possible to see the longitudinal MMP-9 and c-Fn profiles in blood samples in the whole group of patients with acute ischemic stroke. Similar temporal profiles were found in patients with and without m-MCA infarction although higher concentrations of these molecules were observed in m-MCA patients. We agree that the parenchymal and vascular sides of the basal lamina may present different patterns and that data obtained from animal models would be of interest and might be applicable in humans. However, what is being sought for clinical practice is an accurate early marker of m-MCA infarction, which acts to indicate hemicraniectomy, and it seems that plasma samples are sufficiently accurate and precocious as to make this possible although it should be stressed that our data were obtained from a post hoc analysis and so should be considered as hypothesis generating only and requiring confirmation in a large-scale prospective study.
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