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Arteriovenous malformation

Arteriovenous malformation or AVM is a congenital disorder of the veins and arteries that make up the vascular system . The cause of this disorder is unknown, but is not generally thought to be hereditary, unless in the context of a specific hereditary syndrome. more...

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Arteries and veins are part of the human cardiovascular system. Normally, the arteries in the vascular system carry oxygen-rich blood at a relatively high pressure. Structurally, arteries divide and sub-divide repeatedly, eventually forming a sponge-like capillary bed. Blood moves through the capillaries, giving up oxygen and taking up waste products from the surrounding cells. Capillaries successively join together, one upon the other, to form the veins that carry blood away at a relatively low pressure. The heart acts to pump blood from the low pressure veins to the high pressure arteries.

If the capillary bed is thought of as a sponge, then an AVM is the rough equivalent of jamming a tangle of flexible soda straws from artery to vein through that sponge. On arteriorgram films AVM formation often resemble a tangle of spaghetti noodles. This tangle of blood vessels forms a relatively direct connection between high pressure arteries and low pressure veins.

The result is a collection of blood vessels with abnormal connections and without capillaries. This collection, often called a nidus, can be extremely fragile and prone to bleeding. AVMs can occur in various parts of the body including the brain (see cerebral arteriovenous malformation), spleen, lung, kidney and liver. AVMs may occur in isolation or as a part of another disease (e.g. von Hippel-Lindau disease or Rendu-Osler-Weber syndrome).

This bleeding can be devasting, particularly in the brain. They can cause severe and often fatal strokes. If detected before the stroke occurs, usually the arteries feeding blood into the nidus can be closed off, ensuring the safety of the patient.


This condition affected the character of Nate in the US TV series Six Feet Under.


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Immunohistochemical analysis of a cerebral arteriovenous malformation obliterated by radiosurgery and presenting with re-bleeding. Case report
From Neurological Research, 10/1/03 by Szeifert, Gyorgy T

The purpose of this study was to analyze immunohistochemical characteristics of the cell population in a radiosurgically obliterated cerebral arteriovenous malformation (AVM) after recurrent hemorrhage. Immunohistochemical reactions were carried out on paraffin-embedded histological sections for von Willebrand factor (FVIII), CD34 endothelial antigen (CD34), vimentin and alpha-smooth-muscle actin (SMA) cytoskeletal proteins. Histopathological analysis revealed that the majority of AVM channels were replaced by hypocellular scar tissue. However some of them still disclosed thrombus organization by granulation tissue seven years after radiosurgery. FVIII and CD34 reactions revealed vessel neoformation in thrombuses. Proliferating spindle-shaped cells with SMA and vimentin expression were identified in the granulation tissue. These histopathological findings suggest the role of re-canalization in recurrence of hemorrhage following radiosurgical obliteration of the AVM. Contribution of myofibroblastic elements in the vessels' occlusion after radiosurgery is also demonstrated. Neurol Res 2003; 25: 718-721]

Keywords: AVM; radiosurgery; re-bleeding; re-canalization; immunohistochemistry; myofibroblast


Arteriovenous malformations of the brain have been regarded as hamartomatous lesions originating from embryonic maldevelopment1,2. Histologically, they are characterized by clusters of abnormal arteries and arterialized veins with irregular vessel wall structure, and without intervening capillary bed. The first successful treatment of an AVM with radiosurgery was reported by Steiner et al. in 1972(3). Since then, it has become an effective and widespread primary or alternative method in the management of selected cerebral AVMs, especially for those with difficult access for surgery or embolisation4-6. Angiography has been regarded as the standard method to confirm AVM obliteration after radiosurgery7. Although we could find two reports on recurrent hemorrhage after angiographic confirmation of AVM occlusion8,9, immunohistochemical analysis of rebleeding after radiosurgically obliterated AVM has not yet been published. The purpose of this study was to analyze the phenotypic nature of cell population contributing to the obliterative process of the AVM, and in the recurrence of hemorrhage after radiosurgery.


A 25-year-old male patient was admitted with headaches, nausea, vomiting and confusion to another hospital in 1993. CT scan showed a left frontal intracerebral hemorrhage (ICH) bulging into the ventricular horn. Angiography revealed a tiny arteriovenous malformation in the region of the left caudate nucleus with a prominent draining vein towards the deep venous system. Secondary hydrocephalus developed, necessitating ventricular drainage. The AVM was treated with LINAC radiosurgery at an outside institution one month following the onset of the symptoms. The lesion was irradiated with 25 Gy at the 80% isodose line. Because of the persistence of raised intracranial pressure a left occipital ventriculo-peritoneal shunt was inserted. The patient recovered successfully. Occlusion of the AVM nidus was confirmed by control angiography two years later. Seven years after the initial stroke cognitive problems, headaches and memory disturbances occurred. A space occupying, hemorrhagic tumor-like lesion was discovered at the place of the original ICH. A growing mass with contrast enhancement and morphological heterogeneity was observed on serial control CT and MR images (Figure 1A). Repeated angiography did not reveal either a persistent nidus or an early draining vein, but a faint capillary 'blush' at the original locus of the AVM was noticed. Positron emission tomography (with C-11 labeled Methionine) demonstrated increased uptake of the tracer in the same area (Figure 1B). The diagnosis was not clear at that time. Signs of raised intracranial pressure developed due to the mass effect of the lesion. The patient's condition deteriorated, and the lesion was removed totally by emergency surgery craniotomy (Figure 1C). The macroscopic impression was of a hemorrhagic tumor-like tissue at the time of operation (Figure 1D).

The resected specimen was fixed in 10% neutral buffered formaldehyde, processed routinely, and embedded in paraffin. Besides the routine hematoxylin-eosin, van Gieson and Masson's trichrome staining, immunohistochemical reactions were carried out for FVIII, CD34, vimentin and SMA antigens. Biotin-streptavidin-peroxidase complex methods were performed according to standard protocols on 5 [mu]m thick sections. The following antibodies were used in this study: anti-FVIII (Rabbit Anti-Human poiyclonal, DAKO A/S, Denmark) and anti-CD34 (monoclonal Qbend/10, BioGenex, San Ramon, CA, USA) to highlight endothelial layer of the vessels, anti-vimentin (monoclonal V9, BioGenex), and anti-SMA (monoclonal asm-1, Novocastra, Newcastle-upon-Tyne, UK) to characterize cytoskeletal antigens in modified fibroblastic cells.


Histopathological examination of the surgical pathology material revealed a blend of obliterated AVM vessels, recent and elder secondary hemorrhages from recanalization of thrombuses. The majority of AVM vessels were completely replaced by hypocellular, hyalinized scar tissue, without identifiable aperture. At these channels only the contours were discernible. However, some of the AVM vessels showed irregularly stratified wall structure, and although organizing thrombuses obliterated the lumina, they were still recognizable. The thrombuses were in different stages of organization with neovascularization (Figure 2A). Around the newly formed vessels recent and older hemorrhages with hemosiderin production were demonstrated. Intense granulation tissue reaction surrounded and propagated into the thrombuses (Figure 2B). They were rich in thin walled capillaries, fibrocytes, fibroblasts, hemosiderinladen macrophages, and were infiltrated by lymphocytes.

Immunohistochemistry demonstrated prominent FVIII reactivity in the endothelial cells of newly formed rudimentary buds and channels in the obliterating thrombuses of the nonhyalinized AVM vessels (Figure 3A). These neoformations possessed thin, fragile wall structure, and were frequently surrounded by extensive hemorrhages. The rudimentary buds usually consisted of a single FVIII positive cell layer without any further recognizable wall elements. Endothelial cells showing remarkable CD34 positivity were observed in these regions as well, which was most striking in the vessel neoformations of thrombuses (Figure 3B). Areas of the AVM replaced by hyalinized scar tissue did not contain FVIII or CD34 positive cells. The proliferating granulation tissue around and within the thrombuses was abundant in spindle-shaped cells expressing marked vimentin positivity (Figure 3C). The shape of these spindle-shaped cells was identical to fibrocytes or activated fibroblasts. Cells with similar morphological characteristics demonstrated definite SMA immunreactivity as well (Figure 3D). In the hyalinized AVM regions scattered fibrocytes with faint vimentin positivity, but without SMA expression were detected.


Histological characteristics of pathological vessels in cerebral AVMs have been described extensively by previous authors. Following Virchow's fundamental work on pathological description of brain vascular lesions10, the current histopathological classification of cerebral vascular malformations into AVMs, cavernous angiomas, teleangiectasias and venous anomalies was elaborated by McCormick11. Since the role of radiosurgery has been increasing continuously in the neurosurgical realm, unknown complications like tumor induction by low radiation, or re-bleeding of an obliterated AVM might occur in the future.

The goal of radiosurgery is complete nidus occlusion in AVMs. This result is achieved pathologically through a thrombo-obliterative process in the vessels evoked by the ionizing energy of irradiation12,13. Angiographic and MRI examinations have documented that 65%-87% of AVMs are obliterated, and that 75% shrink in volume, 2-5 years after radiosurgery14. However it is not clear from the different series whether there is a significant change in the risk of hemorrhage during the latency period. The risk is higher for larger AVMs and for older patients, and it is lower when higher doses of radiation are used4?15. The totally obliterated nidus and the lack of an early draining vein verified on control angiogram had been previously considered as a cure after radiosurgical treatment of an AVM16. Recently a few cases have been reported with recurrent hemorrhage after angiographie confirmation of AVM occlusion8'9, but they did not supply immunohistological data about the background pathological changes.

Although the annual number of treatments has quadrupled in five years, the histopathological background to radiobiological and pathophysiological effects of radiosurgery has not been fully characterized. A few observations have been published on pathomorphological changes in partially obliterated AVMs after radiosurgery17-19. Blood vessels within the analyzed AVMs showed progressive changes leading to narrowing or occlusion of the lumen. These investigations demonstrate that the obi iterative process starts with endothelial destruction followed by subendothelial and perivascular spindle-shaped cell proliferation in subtotally obliterated AVM vessels after radiosurgery. This proliferation may be connected with thrombus formation. The immunohistochemical characteristics of the proliferating spindle-shaped cells in these studies were identical to myofibroblasts, originally described in granulation tissue during wound healing by Gabbiani et al20. Kondziolka et al.21 anticipated that a similar response would occur in AVMs that proceed to complete obliteration.

Results of the present study correlate with the previous observations that besides thrombus formation, spindle-shaped cells take part in the obliteration and shrinking of the AVM vessels after radiosurgery. The double vimentin and SMA expression in similar cells supports their myofibroblastic nature in the granulation tissue. The single vimentin demonstration in the hyalinized scar tissue areas suggests that resting fibrocytes replace the activated myofibroblasts at the end-stage of the obi iterative process. Scar tissue is a hypocellular, hypometabolic tissue undergoing hyalinization, and constitutes a rigid conglomerate, which might be responsible for stabilization of AVM occlusion following radiosurgery. However, until thrombus organization has not been completed in the vessels, neovascularization may supply a potential source for rebleeding. Yamamoto et al.19 has demonstrated contrast and gadolinium enhancement of the radiosurgically treated AVM nidus by CT and MRI as long as eight years after negative control angiography. This phenomenon might be attributed either to radiation related increased permeability of the AVM vessels' wall, or recanalization and granulation tissue formation, which is rich in capillaries and small arteries. Because of their small caliber relative toother vessels of the AVM, it is unlikely that the presence of recanalized channels could be detected by angiography17,19. The limit to visualize a blood vessel by angiography is 1 mm in diameter21.

The contrast enhancing mass seen seven years later at the site of the treatment might be radiologically so called 'radiation necrosis', however we would prefer the term 'radiation-induced changes'. In a pathological sense necrotic tissue means 'dead tissue' which results in resolution of the tissue at last, i.e. cyst formation. But at the presented case histopathology demonstrated vigorous, proliferating granulation tissue at the site of the 'capillary blush' or 'radiation necrosis' which contained large amount of capillaries, and it might have been responsible for the 'blush' and contrast enhancement.

Regarding the subtotal thrombus organization in spite of the negative control angiography after radiosurgery, the role of PET examination should be considered to assess metabolic activity of AVMs. This sophisticated method detects sensitively metabolic changes of proliferating tissues, like granulation tissue in the presented case. Therefore it might play an important role in the follow up management of radiosurgically treated AVMs, combined with anatomical data of angiography and MRI22.


The authors wish to thank Serge Goldman, MD, PhD, ULB, Hopital Erasme for the PET investigation. This study was supported by the Loterie Nationale, the Ministere de la Politique Scientifique, and th Fonds National de la Recherche Scientifique, Belgium, the Hungarian Ministry of Health & Welfare (ETT-2003).


1 Dandy WE. Arteriovenous aneurysm of the brain. Arch Surg 1928; 17: 190-243

2 Olivecrona H, Landenheim J. Congenital Arteriovenous Aneuryems of the Carotid and Vertebral Arterial Systems, Berlin: Springer, 1957: pp. 10-12

3 Steiner L, Leksell L, Greitz T, Forster DMC, Backlund EO. Stereotaxic radiosurgery for arteriovenous malformations. Acta Chir Scand 1972; 138: 459-464

4 Friedman WA, Blatt DL, Bova FJ, Buatti JM, Mendenhall WM, Kubilis PS. The risk of hemorrhage after radiosurgery for arteriovenous malformations. J Neurosurg 1996; 84: 912-919

5 Lunsford LD, Kondziolka D, Flickinger JC, Bissonette JD, Jungreis CA, Maitz AH, Horton JA, Coffey RJ. Stereotactic radiosurgery for arteriovenous malformations of the brain. J Neurosurg 1991, 75: 512-524

6 Massager N, Regis J, Kondziolka D, Njee T, Levivier M. Gamma knife radiosurgery for brainstem arteriovenous malformations: Preliminary results. J Neurosurg 2000; 93 (Suppl. 3): 102-103

7 Maesawa S, Flickinger JC, Kondziolka D, Lunsford ED. Repeated radiosurgery for incompletely obliterated arteriovenous malformations. J Neurosurg 2000; 92: 961-970

8 Eindqvist M, Karlsson B, Guo WY, Kihlstrom L, Eippitz B, Yamamoto M. Angiographic long-term follow-up data for arteriovenous malformations previously proven to be obliterated after Gamma Knife radiosurgery. Neurosurgery 2000; 46: 803-810

9 Yamamoto M, Jimbo M, Hara M, Saito I, Mori K. Gamma Knife radiosurgery for arteriovenous malformations: Long term follow-up results focusing on complications occurring more than 5 years after irradiation. Neurosurgery 1996; 38: 906-914

10 Virchow R. Die Krankhaften Geschwulste: Dreissig Vorlesungen, gehalten, wahrend des Wintersemesters 1862-1863 an der Universitat zu Berlin. Berlin, Hirschwald, 1863

11 McCormick WF. The pathology of vascular ('arteriovenous') malformations. J Neurosurg 1966; 24: 807-816

12 Szeifert GT, Kemeny AA, Major O, Timperley WR, Forster DMC. Histopathological changes in cerebral arteriovenous malformations following Stereotactic irradiation with the Gamma Knife. In: Kondziolka D, ed. Radiosurgery 1997, Basel: Karger, 1998: pp. 129-136

13 Yamamoto M, Jimbo M, Ide M, Kobayashi M, Toyoda C, Lindquist C, Karlsson B. Gamma Knife radiosurgery for cerebral arteriovenous malformations: An autopsy report focusing on irradiation-induced changes observed in nidus-unrelated arteries. Surg Neurol 1995; 44: 421-427

14 Szeifert GT, Major O, Fazekas I, Nagy Z. Effects of radiation on cerebral vasculature: A review. (Commentary.) Neurosurgery 2001; 48: 452-453

15 Karlsson B, Lax I, Soderman M. Risk for hemorrhage during 2-year latency period following gamma knife radiosurgery for arteriovenous malformations. Int J Radiat Oncol Biol Phys 2001; 49: 1045-1051

16 Lindquist C, Steiner L. Stereotactic radiosurgical treatment of arteriovenous malformations. In: Lunsford LD, ed. Modern Stereotactic Neurosurgery, Boston: Nijhoff, 1988: pp. 491-505 17 Schneider BF, Eberhard DA, Steiner LE. Histopathology of arteriovenous malformations after gamma knife radiosurgery. J Neurosurg 1997; 87: 352-357

18 Szeifert GT, Kemeny AA, Timperley WR, Forster DMC. The potential role of myofibroblasts in the obliteration of arteriovenous malformations after radiosurgery. Neurosurgery 1997, 40: 61-66

19 Yamamoto M, Jimbo M, Kobayashi M, Toyoda C, Ide M, Tanaka N, Lindquist C, Steiner L. Long-term results of radiosurgery for arteriovenous malformation: Neurodiagnostic imaging and histological studies of angiographically confirmed nidus obliteration. Surg Neurol 1992; 37: 219-230

20 Gabbiani G, Ryan GB, Majno G. Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia 1971; 27: 549-550

21 Kondziolka D, Lunsford LD, Flickinger JC. The radiobiology of radiosurgery. Neurosurg Clin N Am 1999; 10: 157-166

22 Leviver M, Wikler D, Goldman S, David P, Metens T, Massager N, Gerosa M, Devriendt D, Desmedt F, Simon S, Van Houtte P, Brotchi J. Integration of metabolic data of positron emission tomography in the dosimetry planning of radiosurgery with the Leksell Gamma Knife: Early experience with brain tumors. J Neurosurg 2000; 93 (Suppl 3.): 233-238

Gyorgy T. Szeifert*, Isabelle Salmon, Danielle Baleriaux, Jacques Brotchi and Marc Levivier

Centre Gamma Knife, Universite Libre de Bruxelles, Hopital Academique Erasme, Brussels, Belgium * National Institute of Neurosurgery, Budapest, Hungary

Correspondence and reprint requests to: Prof. Marc Levivier, MD, PhD, Centre Gamma Knife, Universite Libre de Bruxelles, Hopital Erasme, Route de Lennik 808, B-1070 Brussels, Belgium.

[] Accepted for publication March 2003.

Copyright Forefront Publishing Group Oct 2003
Provided by ProQuest Information and Learning Company. All rights Reserved

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