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Neuroimaging studies of postobliteration nidus changes in cerebral arteriovenous malformations treated by gamma knife radiosurgery
ELSEVIER
Radiosurgery
NEUROIMAGING STUDIES OF POSTOBLITERATION NIDUS CHANGES IN CEREBRAL ARTERIOVENOUS MALFORMATIONS TREATED BY GAMMA KNIFE RADIOSURGERY Masaaki Yamamoto, M.D., Mitsunobu Ide, M.D., Minoru Jimbo, M.D., Kintomo Takakura, M.D., Christer Lindquist, M.D., Ph.D., and Ladislau Steiner, M.D., Ph.D. Departments of Neurosurgery, Dai-ni Hospital and Neurological Institute, Tokyo Women’s Medical College, Tokyo, Japan; Karolinska Hospital, Stockholm, Sweden; and University of Virginia Health Sciences Center, Charlottesville, Virginia
Yamamoto M, Ide M, Jimbo M, Takakura K, Lindquist C, Steiner L. Neuroimaging studies of postobliteration nidus changes in cerebral arteriovenous malformations treated by gamma knife radiosurgery. Surg Neurol 1996;45:110-22. BACKGROUND Following radiosurgical treatment, the majority of patients with arteriovenous malformations (AVMs) are periodically examined by means of computed tomography (CT) and magnetic resonance imaging (MRI) to assess the attainment of nidus obliteration, as well as adverse radiation effects in the surrounding brain. However, few neuroimaging studies of the long-term results following complete obliteration, confirmed by angiography, have been published to date. METHODS CT, MRl, magnetic resonance (MR) angiographic and angiographic images, obtained after angiographic confirmation of complete nidus obliteration, were reviewed in 11 AVM patients treated with gamma knife radiosurgery. The period between angiographic confirmation of nidus obliteration and these most recent examinations was 12-84 months (mean, 29 months). RESULTS In ten patients who were assessed by CT, the obliterated nidus was shown to be isodense (eight cases) or a mixture of isodense and hypodense areas (two cases). A significant time-related decrease in contrast enhancement was observed within 1 to 2 postobliteration years (five/seven cases). Eight patients were evaluated by MRI. On T,-weighted imaging, the nidus was shown to be hypointense (six cases) or a mixture of hypointense and isointense areas (two cases). On T,-weighted imaging, nidus intensity varied more than that observed on T,Address reprint requests to: Masaaki Yamamoto, M.D., D.M.Sc., Department of Neurosurgery, Tokyo Women’s Medical College Dai-ni Hospital, Z-1-10 Nishiogu. Arakawa-ku, Tokyo 116, Japan. Received January 26, 1995; accepted July 27, 1995. 0090-3019/96/$15.00 SSDI 0090-3019(95)00382-7
weighted imaging, and time-related intensity increases were observed (two/seven cases). No flow-signal void was demonstrated in any of these cases. In four of the seven cases, in which serial postobliteration follow-up MRl studies were conducted, significant gadolinium enhancement persisted 3 years or more after obliteration (maximum of 7 years). No vascular abnormalities were demonstrated in seven patients who were assessed by conventional angiography and/or MR angiography. CONCLUSIONS Radiosurgery-induced changes in a nidus may continue for several years after angiography has shown complete AVM obliteration. KEY WORDS Arteriovenous malformation, gamma knife, radiosurgery, computed tomography, magnetic resonance imaging, enhancement.
R
adiosurgery using a gamma knife, a recently developed linear accelerator system, or a system using the Bragg peak proton beam, is now a well-established treatment alternative for small arteriovenous malformations (AVMs), which are considered to be inoperable because of their location in critical brain regions, and for patients in whom other medical factors contraindicate surgery [ 1,2, 4-8,10-12,14,16-l&20,21,23,27-29,321. Overall, approximately 80% of patients show complete angiographic obliteration within a latency period of 2 to 3 years. To our knowledge, there are no reports of hemorrhage occurring after angiographic demonstration of nidus obliteration [7,8,12,16-18,20,2629]. Thus, it is widely accepted that angiographi655 Avenue
0 1996 by Elsevier Science Inc. of the Americas, New York, NY 10010
Postobliteration
Changes in Gamma Knife-Treated AVMs
tally confirmed disappearance of the nidus should be the goal in all AVM patients treated radiosurgitally [ 8,17,20]. Following radiosurgical treatment, therefore, the majority of patients are periodically examined by means of computed tomography (CT) and magnetic resonance imaging (MRI) to assess the attainment of this treatment goal, as well as adverse radiation effects in the surrounding brain [9,20,22-24,28,33]. However, few CT scan and MRI studies of the long-term results following complete obliteration, confirmed by angiography, have been published to date. In particular, relatively little information is available on postobliteration, timerelated changes in nidus enhancement, contrast enhancement on CT scan, and gadolinium enhancement on MRI. Several animal experiments in which radiosurgery-induced changes within the irradiated normal brain are analyzed using postcontrast CT scan and/or postgadolinium MRI have been reported [3,19,25]. In these experiments, however, neuroimaging follow-up studies were discontinued within 63 postradiosurgical weeks. In this study, postobliteration neuroimaging findings following angiographically confirmed nidus obliteration were retrospectively analyzed in 11 AVM patients treated with a gamma knife. Based on the limited number of patients in this series, as well as the histologic findings of the radiosurgically obliterated AVM reported previously [32], we briefly discuss pathologic changes in postobliteration AVMs, which are ongoing for at least 5-6 years after radiosurgery; these observations may resolve the debate, which has presented arguments against radiosurgical AVM treatment, as to whether radiosurgery alone changes the nidus from an angiographically visible to an occult AVM.
MATERIALANDMETHODS PATIENT
POPULATION
Among 30 patients with AVMs treated by means of gamma knife radiosurgery during the period from 1978 to 1992, complete nidus obliteration has thus far been angiographically demonstrated in 20 cases between 1 and 5 years after the radiosurgical treatment. In 11 of these 20 patients, CT, MRI, MR angiography, and conventional angiography were performed more than 1 year after angiographic confirmation of nidus obliteration (Table 1). The patients ranged in age from 9 to 54 years (mean, 23 years) at the time of radiosurgery. There were eight females and three males. The AVM manifested with intracranial hemorrhage in all cases. The location of the nidus was supratentorial in ten cases and in-
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Postobliteration Findings on Computed Tomography nance Angiography (MRA), and Angiography
(CT), Magnetic
INTENSITY
CASE
AGE/ PERIODS CONTRAST T,DENSITY ENHANCEMENT WEIGHTED No. SEX (MO) 1
14/F
13
2
10/F
12
3
30/F
5
6
9/F
19/F
13/F
28/M 47/M 26/M
T2WEIGHTED
Complete obliteration Complete obliteration
_
+ + _ _
HYPE HYPE
Hype
_ _
+ +
Hype HYPOHYPO-
HYPE Hype - hyper-
1s~ - hype
+ + +
_ _
+ + +
Is@* Hyper-* 1so-* 1so-*
++ +++ ++ +
HYPOHYPE- Hypo- HYPE HYPE- -
Hype- - hyperHypoHype Hype - hyperHype - hyper-
_ _ -
+ +++ +++ +++ +++
48 17 12 0 16
1so-* Isc- - hypo-
? +
Hype - iso
Hype- - hyper-
-
++
ISO-
2 + 5
HYP@ Hype-
Hype- - hyperHyper-
-
+++ +
0 14 0 15
kSCF*
HYPOHyPo Hype - iso Hype- - iso
HypoHype Hype Hype
-
+ + + +
0 17
ISO-
44 0 14
ISO-
34 0 14
+
Iso- - hypo-
Is0 IS@
Reso-
MRA OR FLOW t%DOLINRJM ANGlOGRAPHIC VOID ENHANCEMENT FINDINC~~~
HyperHYPOHyPo HYPO-
+ + _
84 4 10 34
::
7 8 9
Imaging (MRI), Magnetic
MRI F’INDMGS
CT FINDINGS
4
Resonance
et al
HYP* HypeHypeHYPE
iso iso isoiso-
No vascular abnormalities No vascular abnormalities
No vascular abnormalities
No vascular abnormalities
No vascular
abnormalities 10
22/F
11
38/F
ISO-*
+ _ ++ +
ISOIS@
*Period (mo; month) between angiographically confirmed
obliteration. *Calcification.
+, contrast
or gadolinium
enhancement;
obliteration
GAMMA KNIFE TREATMENT Nine patients underwent gamma knife radiosurgery at the Karolinska Hospital, Stockholm, one patient (case 10) at the University of Tokyo, Tokyo, and the one remaining patient (case 11) at the Heisei Memorial Hospital, Fujieda. The gamma knife treatment was optimal in 10 cases, the nidus was com-
hyper hyperhyperhyper-
and the examination.
-, negative; ?, equivocal;
fratentorial in the one remaining case. The preradiosurgical nidus volume ranged from 0.15 cm3 to 24.15 cm3, with a median of 1.05 cm3. None of the patients had previously undergone either fractionated external beam radiation or interventional radiology. However, a cerebrospinal fluid shunt operation had been carried out in three cases and a craniotomy in two.
-
BMRA, no vascular
+, slight; + +, moderate;
abnormalities;
angiography,
complete
+ + +, marked.
pletely covered, and 20 gray (Gy) or more was given at the periphery [29]. In the one remaining case (case 7) the nidus could not be completely covered due to its size. The selected target dose given at the periphery was 25 Gy or more in 6 cases, 20-25 Gy in 4, and less than 20 Gy in 1 case. NEUROIMAGING FOLLOW-UP The latency interval from treatment to angiographitally confirmed obliteration of the AVM varied from 9 to 39 months, with a mean of 21 months. Thereafter, CT scan and/or MRI were periodically performed in 10 cases. The period between angiographic confirmation of nidus obliteration and these most recent examinations was 12-84 months (mean, 32 months) and that between gamma knife
Postobliteration
Changes in Gamma Knife-Treated
Case 2. Left vertebral •Btion in the temporal nidus obliteration
AVMs
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angiogram obtained before gamma knife radiosurgery showing an arteriovenous malformalobe (A). Left vertebral angiogram obtained 12 months after irradiation showing complete
(B).
treatment and these most recent examinations was 24-96 months (mean, 51 months). All CT scans (axial, precontrast and postcontrast) and MRI (axial, T,-weighted, T,-weighted, and postcontrast T,weighted; gadolinium-diethylenetriamine pentaacetic acid [Cd-DTPA]) were obtained with a section thickness of 5 mm. In performing MRI, a 1.5-Tesla MR imager (MRT 2OOFX, Toshiba Medical, Tokyo) was used. Imaging parameters for these studies included a repetition time (TR) of 500 msec and an echo time (TE) of 15-20 msec for T,-weighted image, and a TR of 2000 msec and a TE of 80 msec for T,-weighted image. In two patients (cases 1 and 2) who underwent radiosurgical treatment in the early 1980s conventional angiography was repeated 1 year after angiographic confirmation of nidus obliteration. In five cases, threedimensional time-of-flight MR angiography, using the MR imager mentioned above, was performed at some point between 16 and 36 months postobliteration (mean, 23 months). Imaging parameters for these studies included a TR of 35 msec, a TE of 8 msec, a flip angle of 30 degrees, matrix of 256 X 192, and section thickness of 1.6 mm X 32 slices. Two images, a sagittal section and a semicoronal section, were routinely obtained.
RESULTS Table 2 summarizes postobliteration findings on CT scan, MRI, MR angiography, and conventional angiography. Among 10 patients who were assessed by CT, the
obliterated nidus was shown to be isodense in eight, and a mixture of isodense and hypodense areas in the other two. Calcification was identified in four cases, in one (case 2) of whom no calcification had been seen on CT scan before gamma knife treatment (Figures 1 and 2). Among seven cases in whom serial postoperative follow-up CT studies were performed, no postobliteration density changes were observed in six cases. In the one remaining case (case 6) however, remarkable postobliteration density changes were observed, an increase followed by a subsequent decrease, recognizable through the end of the second postobliteration year (Figures 3 and 4). In five of the seven cases, a significant time-related decrease in contrast enhancement was observed 1 to 2 years after angiographically confirmed nidus obliteration. Eight patients were evaluated by MRI. On T,weighted imaging, the nidus was shown to be hypointense in six cases and a mixture of hypointense and isointense areas in the two remaining cases. On T,-weighted imaging, however, nidus intensity was more varied than that on T,-weighted imaging: hyperintense in two, hypointense in two, and a mixture of hyperintense and hypointense areas in the four remaining cases. No flow-signal void was demonstrated in any of these cases. Following gadolinium administration, the nidus was enhanced in seven of the eight cases. In the remaining case, however, remarkable enhancement was observable by the fourth postobliteration month, and thereafter disappeared. In seven cases, serial postobliteration follow-up MRI studies were conducted. No
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Case 2. CT scans obtained before radiosurgical treatment showing equivocal contrast enhancement and no calcification (A: left, precontrast CT scan; right, postcontrast CT scan). CT scans and MRl obtained 84 months after angiographic confirmation of nidus obliteration showing the calcified nidus to be enhanced moderately by contrast material and significantly by gadolinium (IS: from left, precontrast CT scan, postcontrast CT scan, T,-weighted MRI, postgadolinium T,-weighted MRl and T,-weighted MRi).
time-related intensity changes were observed on T,-weighted imaging, though time related intensity increases were observed on TX-weighted imaging in two (cases 6 and 9) of the seven cases (Figures 4 and 6). In only two (cases 3 and 9) of the seven cases, a time-related decrease in gadolinium enhancement was observed following angiographitally confirmed nidus obliteration (Figures 5 and 6). In four cases (cases 2,4, 5, and S), significant gadolinium enhancement persisted 3 years or more (maximum, 7 years) after angiographic confirmation of nidus obliteration (Figures 2 and 4). In seven patients who were evaluated by conventional angiography or MR angiography, the absence of vascular abnormalities was confirmed.
DISCUSSION Radiosurgical treatment can result in AVM obliteration after a 1 to 3-year latency period [1,2,4-8,1012,14,16-l&20,23,26-29,32]. This radiosurgically induced change within an AVM is considered to occur as follows: a beam of ionizing radiation initially injures the endothelial cells of vessels, which in-
duces, as a reparative process, a gradual thickening of connective tissue within the intima. This intimal hypertrophy eventually obstructs the lumina of vessels within the AVM [10,27,32]. We have already reported an autopsy case with an AVM treated by gamma knife radiosurgery, in which postmortem studies following AVM-unrelated death were performed after 2-year angiography had demonstrated complete nidus obliteration [32]. In this case, we observed that many of the AVM vessels had obstructed lumina owing to intimal hypertrophy. It was also noted that some of the vessels had patent lumina as well as persistent and recanalizing vessels, which could not be observed angiographically. We also observed evidence of exudation of albuminous fluid in the nidus. Both patent blood flow and serum exudation could be considered to reflect the increased uptake of contrast material and Gd-DTPA within the treated nidus. Furthermore, the most important finding disclosed by this autopsy case is that reconstructive and destructive processes continue within the radiosurgically thrombosed nidus. In this investigation, we analyzed subsequent changes in the nidus demonstrated by means of
Postobliteration
Changes in Gamma Knife-Treated AVMs
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Case
6. (A) Left carotid angiogram obtained before gamma knife radiosurgery showing an arteriovenous malformation in the thalamus. (B) Left carotid angiogram obtained 26 months after irradiation showing complete nidus obliteration.
neurodiagnostic imaging techniques following angiographically confirmed nidus obliteration. Although there are a few exceptional cases, postobliteration CT and MRI findings of the nidus can be summarized as follows: The nidus is isodense or a mixture of isodense and hypodense areas on CT, except for areas of calcification. Postcontrast CT shows enhancement, either remarkable or moderate, within 1 to 2 years after angiographic confirmation of nidus obliteration. This nidus enhancement tends to disappear thereafter. T,-weighted MRI reveals hypointensity and/or isointensity. Although intensity varies on Tzweighted MRI, a hyperintense area tends to appear or to increase in size within the nidus with the passage of time. Significant gadolinium enhancement at the site of the treated nidus, which, along with the absence of flow-signal void, can be considered to suggest complete obliteration [ 23,321, tends to persist
for several years following angiographic mation of nidus obliteration.
confir-
Debate continues as to why significant gadolinium enhancement of the treated nidus on MRI persists even after disappearance of contrast enhancement on CT scan (Figures 2 and 4), since Cd-DTPA diffusion in the setting of a disrupted blood-brain barrier is considered to be similar to that of iodinated contrast media [4]. Nevertheless, image reconstruction and the contrast mechanisms of CT and MRI are quite different. Paramagnetic contrast agents like gadolinium do not specifically produce a signal, but rather act indirectly by changing the intrinsic magnetic properties of protons. Because of the exponential relationship, very small amounts of GdDTPA result in dramatic change in signal intensity [30]. In contrast, small amounts of contrast media produce only slight increases in X-ray attenuation, which is undetectable on routine CT examination. As shown in cases 3, 6, and 9, gadolinium enhancement decreases and may ultimately disappear if the flow of
1 Case 6. CT scans and MRI obtained at the time of angiographic confirmation of nidus obliteration (A), and 12 El months (B), 24 months (C), 36 months (D), and 48 months (E) after obliteration (from left, precontrast CT scan, postcontrast CT scan, T,-weighted MRI, postgadolinium T,-weighted MRI, and T,-weighted MRI). Note: 1. Serial follow-up CT scans show postobliteration nidus changes in density and contrast uptake, an increase followed by a subsequent decrease, through the 24th postobliteration month (A,B,C).2. Significant gadolinium enhancement of the nidus on MU1persisted, though contrast enhancement was unremarkable on CT scan throughout 48 months following obliteration @, E). However, a slight decrease in gadolinium enhancement was observed between 36 and 48 postobliteration months (D, E). 3. A gradual increase in the hyperintense area on T,-weighted MRI was observed (B, C).
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9. (A) Right carotid angiogram obtained during gamma knife radiosurgery showing an arteriovenous la Case malformation in the thalamus. @I)Left carotid angiogram obtained 24 months after irradiation showing complete
nidus obliteration.
Gd-DTPA to the treated nidus is completely stopped due to obliteration of all AVM-related vessels. These results show that radiosurgery-induced changes in the nidus may continue for several years after angiography has demonstrated complete AVM obliteration, although the most remarkable changes have generally occurred by the end of the second radiosurgical year [24,31]. Based on the limited number of patients in this series, as well as the autopsy findings mentioned above, these late changes can be considered to involve further obliteration of the remaining or recanalizing vessels and to reflect an ongoing process from coagulation necrosis to liquefaction necrosis. Relatively early decreases in nidus enhancement on postcontrast CT may be attributable to further obliteration of patent vessels. Increased fluid in the extracellular space can contribute to persistent nidus enhancement by Gd-DTPA and an increase in the hyperintense area demonstrated by T,-weighted MRI (Figures 4 and 6). The two following issues must be taken into consideration in light of these results. First, radiosurgically induced nidus obliteration differs fundamentally from angiographically occult vascular malformation (AOVM), which can also be treated by radiosurgery [ 13,151. Unfortunately, the debate as to whether radiosurgery alone changes the nidus from an angiographically visible to an occult AVM has yet to be resolved. Although AOVM is an active lesion and has the potential to bleed before treatment has been carried out, a nidus that has been obliterated by radiosurgery is undergoing a degen-
erative process, leading to liquefaction necrosis, and, therefore, is considered to have less potential for bleeding. Second, in some cases in which 2- or S-year angiography shows a very small residual nidus, slow though complete obliteration can be expected over several years. Therefore, the second course of gamma knife treatment can be postponed for 5 to 6 years following the initial irradiation. We did, in fact, experience a case of complete obliteration confirmed 5 years after irradiation, despite only partial obliteration at the time of 3-year angiography [10,31]. Recently, Pollock et al [23] also reported a patient, whose nidus was angiographitally shown to be partially obliterated 48 months after treatment, in whom complete obliteration was demonstrated at 65 months. Serial follow-up CT scans in case 6 showed postobliteration density changes, an increase followed by a subsequent decrease, through the end of the second postobliteration year. As is well known, a transiently evident attenuation increase on CT scans can be caused by bleeding or a transient increase in blood flow. This patient presented no symptoms suggesting intracerebral hemorrhage when these examinations were performed 1 year after obliteration, although very mild hemorrhage producing no clinical symptoms is possible. However, corresponding to this attenuation increase, a postcontrast CT scan obtained at the same time showed the nidus to be more enhanced than that obtained at the time of obliteration. Subsequent follow-up examinations demonstrated gradual decreases in contrast enhancement. An increased dis-
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Case 9. CT scans and MRl obtained at the time of angiographic confirmation of obliteration showing the nidus to q * be significantly enhanced by gadolinium, despite minimal contrast enhancement, and a T,-weighted image demonstrating hyperintense edema surrounding the nidus (A:from left, precontrast CT scan, postcontrast CT scan, T,-weighted MRI, and T,-weighted MRI). CT scans and MRI obtained 16 months after angiographic confirmation of nidus obliteration showing equivocal enhancement by gadolinium as well as contrast media, and, on T,-weighted MRI, appearance of a hyperintense area within the formerly shown hypointense area and disappearance of hyperintense areas, indicating the adverse effects of radiation (B: from left, precontrast CT scan, postcontrast CT scan, T,-weighted
MRI, postgadolinium T,-weighted MRI, and T,-weighted MRI).
ruption of the blood-brain barrier may be the most feasible explanation. However, the possibility that there were increases in blood flow within the treated nidus following angiographic confirmation of nidus obliteration still cannot be completely ruled out. The authors would like to thank Shunsuke Kawamoto, M.D., Department of Neurosurgery, University of Tokyo, and Tatsuo Hirai, M.D., Heisei Memorial Hospital, forgamma knife treatment, and Mr. Masato Goto, Department of Radiology, Toda Chuo Hospital, for his collaboration in the MR study. The authors are also very grateful to Bierta E. Barfod, M.D., University of Washington School of Medicine, for her assistance in prooheading the English manuscript. This study was supported by scholarships from the Royal Swedish Academy of Sciences, the Japanese Society for the Promotion of Science, the Japan Private School Promotion Foundation, and the Dr. hoe Okamoto International Exchange Fund.
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COMMENTARY
It has always seemed strange to me that there are thousands of patients who have been treated at the Karolinska Institute for a period that exceeds 20 years, and yet we have no factual follow-up on these patients, just suppositions which are turned into facts along with recent reviews of the experience of the past few years. Regarding this particular paper, I believe that it should be published because many of the statements are controversial. First of all, I was pleased to see that the authors admit that only 80% of the small AVMs show com-
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plete angiographic obliteration after a latency period of 2-3 years. This is contrary to the opinion presented by many radiosurgeons, including Steiner and Lunsford, where the obliteration rate is estimated higher. According to them, small AVMs are obliterated in 90%-95% of the cases. 1 was also pleased to see that the authors of this manuscript accept the fact that angiographically confirmed disappearance of the nidus should be the goal in all AVM patients who are treated by radiosurgery. Does the same apply to cavernous malformations, which they say can be treated by radiosurgery? What is the endpoint in terms of these later lesions? In analyzing the materials in this paper, they started out with 30 patients during a period of 4 years. I assume that all these patients had small AVMs. They had angiographically demonstrated that 20 of the 30 patients had complete nidus obliteration. For some reason, they took 11 of the 20 patients and studied the MRI, MRA, and conventional angiograms, more than 1 year after angiographic confirmation. Why they chose 11 rather than all 20 patients is beyond my comprehension. They then present a litany on the effect of radiation as it relates to the volume of the AVM. This use of volumetric analysis is confusing. I think that it is very hard to obtain a volumetric analysis from twodimensional studies. It sends the wrong message. I believe that we should stick to the maximum diameter in terms of analyzing our materials. To get to the meat of the paper, they are basically using MRI, MRA, and CT scan data to show dynamic changes in the AVM in response to radiosurgery and not using it solely to analyze obliteration of the nidus. I feel that we must stick to the gold standard of using angiography to determine if the AVM is obliterated by whatever technique is utilized. The MRI is not infallible and may be misleading, and a CT scan is even worse. There are certain terms that are used regarding the changes that they presume are occurring within the AVM nidus. For example, they indicate that the neuroimaging (MRI and CT) may show dynamic changes for several years after angiographic occlusion of the AVM. They relate the changes to “further obliteration of the remaining or recanalizing vessels.” If vessels are remaining or recanalizing, it would seem to me that they should be recognized on the angiogram. Therefore, their complete obliteration would not be seen on the angiogram. The authors’ explanation for this contrariness is not given in the paper. They also point out the vagaries of AVM obliteration by radiosurgery in mentioning a case in which the AVM was not obliterated in 3 years, but in 5 years. Therefore, how are we to know which cases
Yamamoto et al
will be treated successfully by radiosurgery (20% are not)? At what particular time might we expect obliterations? Furthermore, no mention is made of imaging changes that might suggest radiation damage to the surrounding tissues. We have certainly seen these changes frequently at various periods of time after radiosurgery. Some of these changes are reversible, but unfortunately others are not. Discussion of this aspect of radiosurgery is minimized in the literature and is not addressed in this particular manuscript. Finally, they suggest that cavernous malformations can be treated successfully by radiosurgery. They cite two references: one is a preliminary report, and the other is in press in the Japanese literature. I believe that this is another example of wish fulfillment, whereby a wish is turned into a fact. The literature is replete with references to the radiosurgical treatment of cavernous malformations and is overwhelmingly in favor of not using this treatment, since there is no endpoint to determine success. There has been a higher percentage of radiation damage as it relates to the treatment of cavernous malformations and venous malformations than AVMs, a fact which has been mentioned by Dr. Steiner. In spite of the fallacies of literature supporting radiosurgery (this seems to be a generic problem), they should be published, but they should be taken to task at the same time. Bennett M. Stein, M.D. New York, New York This paper is on neuroimaging in post-gamma knife treatment of AVMs. It shows that the CT and MRl appearances can differ and change over time following nidus obliteration. However, many of their patients had different appearances over time and the conclusions that one can draw from the imaging findings are, in my mind, questionable. Furthermore, the explanations and rationale that the authors give for the varying MRI and CT appearances are speculative in some instances, and far from convincing in others. One particular problem is that the authors state that late changes are considered to reflect further obliteration of the remaining or recanalizing vessels, supposedly an ongoing effect of the radiation; however, are the authors absolutely certain that there was no recanalization of viable AVM nidus? Though there are 11 cases in the study, there are only 3 or 4 cases that were serially followed for a significant period of time. Therefore, the conclusions drawn about long-term follow-up are based
Postobliteration
Changes in Gamma Knife-Treated AVMs
upon a very small number of patients. Any conclusions made would have been more valid if more of their patients had been followed serially for longer periods of time. Also, the stated goal of their introduction is to resolve an ongoing debate about the conversion of an AVM to an occult AVM with radiosurgery; it is not clear that they can make such claims or resolve such a debate, given that not one of their patients was pathologically studied. This is especially true given that none of the long-term follow-ups had angiographic analysis. In addition, all of the patients presented with AVM-related hemorrhage. Nowhere in their explanation of MRI evolution do they mention that some of the changes could be related to hemorrhage and the evolution of blood. Where does this fit into their explanation of MRI findings? The tail end of the “Results” section, in which a description of the MRI changes is given, is convoluted and difficult to make any kind of sense of. The discussion of the physiologic effects of the radiosurgery on an AVM is good and instructive. However, the translation of these known effects into an explanation of the imaging findings is not logical or readily understood, in my opinion. For example, patent blood flow and serum exudation might be considered an explanation, but certainly not a reflection, of increased contrast or gadolinium uptake with a treated nidus. It appears from the authors’ bibliography that the post-gamma knife treatment of AVMs and the appearance on CT and MRI have already been described, so it is not clear to me that the authors have described anything new, at least as far as the early and subacute imaging findings go. Again, the explanations offered for the continued MRI enhancement of these nidi as a reflection of late radiation-induced changes is, in my mind, questionable. Once again, it is not clear that the authors have excluded recanalization of nidus vessels. In particular, figure 4E looks like flow voids to me, and I would wonder what an angiogram of this case would show at 48 months. In the end, I found myself unconvinced after reading this paper that the authors had made a significant contribution, or that their contentions were borne out by the imaging findings. Lawrence E. Ginsberg, M.D.
Houston, Texas Dr. Yamamoto and his colleagues have taken a distinct interest in the definition of the process of AVM obliteration after radiosurgery, its timing, and the
Surg Neurol 1996;45:1lo-22
12 1
imaging sequelae that accompany it. They have raised a number of interesting points in prior publications, and these are amplified in the present report. Imaging after successful radiosurgery must define angiography obliteration in order to be absolutely sure of the elimination of risk of AVM hemorrhage. Emerging evidence supports the concept that nidus obliteration, even in the presence of a residual early draining vein, may also be associated with complete or almost complete AVM protection. This may be related to the absence of significant AVM shunting, and the likelihood that over time the AVM itself will completely obliterate. Yamamoto and his associates have studied 11 patients who had successful obliteration of their AVMs confirmed by angiography with a defined latency interval. Subsequent imaging studies were then performed to assess the time course of the associated imaging changes. We support Yamamoto’s concept that the appearance of contrast opacification (in the absence of flow-void signal on MRI scan) is highly correlated with successful complete angiographically defined obliteration. We have also seen other patients who have had persistent evidence of contrast enhancement at the target site after AVM obliteration has been confirmed by angiography. However, in most, patients the contrast enhancement slowly fades over time and is present most commonly on or about the time of AVM obliteration. The reasons for blood-brain barrier breakdown at the target volume are not completely clear, and whether they represent neovascularization into a fibrotic area, or leaky capillaries that subsequently resolve over time, has as yet been unanswerable, primarily because such patients do not undergo histopathologic studies. I believe that this report helps to reassure referring and treating physicians that radiosurgery can be associated with recognizable imaging sequelae, and that such sequelae are often associated with clinical relevance. The absolute causes of these imaging changes await further pathologic and radiobiologic studies. L. Dade Lundsford, M.D.
Pittsburgh, Pennsylvania
The authors provide an interesting neuroimaging study of postobliteration nidus changes in cerebral AVM, which have been treated by gamma knife radiosurgery. In their abstract, the authors state that they intend to discuss the ongoing pathologic changes in postobliteration AVMs that occur for at least 5 to 6 years following radiosurgery. This is a difficult goal to achieve, since no pathologic speci-
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mens were examined in this report. What the authors report are the ongoing radiologic changes in the region of the brain that is exposed to gamma radiation during treatment of small cerebral AVMs. The authors they draw speculative conclusions as to what they radiographic developments represent on a histologic level. It is problematic that none of their “long-term” follow-up patients were studied with cerebral angiography, which would have been useful in determining if some of the MRI findings were related to slow recanalization of the malformation. Without the use of arteriography, it is difficult to assume that no recanalization has occurred. The discussion of the MRI findings in the brain following gamma knife therapy is interesting, but adds very little credence to the sketchy scientific basis for the conclusions drawn. Some of the
radiologic changes seen on MlU scanning over the ensuing years could also be related to resolution of microscopic parenchymal hemorrhages surrounding the vascular malformations. This manuscript nicely demonstrates that illdefined radiologic changes are visualized with MRl scanning and continue years after angiographic obliteration of small AVMs by gamma knife radiosurgery. It is uncertain what these changes represent, and until such time as angiography is performed on truly long-term follow-up, recanalization of the vascular malformation cannot be excluded as a possibility. Thomas A. Kopitnik, Jr., M.D. Duke Samson, M.D.
Dallas, Texas
Radiosurgery
NEUROIMAGING STUDIES OF POSTOBLITERATION NIDUS CHANGES IN CEREBRAL ARTERIOVENOUS MALFORMATIONS TREATED BY GAMMA KNIFE RADIOSURGERY Masaaki Yamamoto, M.D., Mitsunobu Ide, M.D., Minoru Jimbo, M.D., Kintomo Takakura, M.D., Christer Lindquist, M.D., Ph.D., and Ladislau Steiner, M.D., Ph.D. Departments of Neurosurgery, Dai-ni Hospital and Neurological Institute, Tokyo Women’s Medical College, Tokyo, Japan; Karolinska Hospital, Stockholm, Sweden; and University of Virginia Health Sciences Center, Charlottesville, Virginia
Yamamoto M, Ide M, Jimbo M, Takakura K, Lindquist C, Steiner L. Neuroimaging studies of postobliteration nidus changes in cerebral arteriovenous malformations treated by gamma knife radiosurgery. Surg Neurol 1996;45:110-22. BACKGROUND Following radiosurgical treatment, the majority of patients with arteriovenous malformations (AVMs) are periodically examined by means of computed tomography (CT) and magnetic resonance imaging (MRI) to assess the attainment of nidus obliteration, as well as adverse radiation effects in the surrounding brain. However, few neuroimaging studies of the long-term results following complete obliteration, confirmed by angiography, have been published to date. METHODS CT, MRl, magnetic resonance (MR) angiographic and angiographic images, obtained after angiographic confirmation of complete nidus obliteration, were reviewed in 11 AVM patients treated with gamma knife radiosurgery. The period between angiographic confirmation of nidus obliteration and these most recent examinations was 12-84 months (mean, 29 months). RESULTS In ten patients who were assessed by CT, the obliterated nidus was shown to be isodense (eight cases) or a mixture of isodense and hypodense areas (two cases). A significant time-related decrease in contrast enhancement was observed within 1 to 2 postobliteration years (five/seven cases). Eight patients were evaluated by MRI. On T,-weighted imaging, the nidus was shown to be hypointense (six cases) or a mixture of hypointense and isointense areas (two cases). On T,-weighted imaging, nidus intensity varied more than that observed on T,Address reprint requests to: Masaaki Yamamoto, M.D., D.M.Sc., Department of Neurosurgery, Tokyo Women’s Medical College Dai-ni Hospital, Z-1-10 Nishiogu. Arakawa-ku, Tokyo 116, Japan. Received January 26, 1995; accepted July 27, 1995. 0090-3019/96/$15.00 SSDI 0090-3019(95)00382-7
weighted imaging, and time-related intensity increases were observed (two/seven cases). No flow-signal void was demonstrated in any of these cases. In four of the seven cases, in which serial postobliteration follow-up MRl studies were conducted, significant gadolinium enhancement persisted 3 years or more after obliteration (maximum of 7 years). No vascular abnormalities were demonstrated in seven patients who were assessed by conventional angiography and/or MR angiography. CONCLUSIONS Radiosurgery-induced changes in a nidus may continue for several years after angiography has shown complete AVM obliteration. KEY WORDS Arteriovenous malformation, gamma knife, radiosurgery, computed tomography, magnetic resonance imaging, enhancement.
R
adiosurgery using a gamma knife, a recently developed linear accelerator system, or a system using the Bragg peak proton beam, is now a well-established treatment alternative for small arteriovenous malformations (AVMs), which are considered to be inoperable because of their location in critical brain regions, and for patients in whom other medical factors contraindicate surgery [ 1,2, 4-8,10-12,14,16-l&20,21,23,27-29,321. Overall, approximately 80% of patients show complete angiographic obliteration within a latency period of 2 to 3 years. To our knowledge, there are no reports of hemorrhage occurring after angiographic demonstration of nidus obliteration [7,8,12,16-18,20,2629]. Thus, it is widely accepted that angiographi655 Avenue
0 1996 by Elsevier Science Inc. of the Americas, New York, NY 10010
Postobliteration
Changes in Gamma Knife-Treated AVMs
tally confirmed disappearance of the nidus should be the goal in all AVM patients treated radiosurgitally [ 8,17,20]. Following radiosurgical treatment, therefore, the majority of patients are periodically examined by means of computed tomography (CT) and magnetic resonance imaging (MRI) to assess the attainment of this treatment goal, as well as adverse radiation effects in the surrounding brain [9,20,22-24,28,33]. However, few CT scan and MRI studies of the long-term results following complete obliteration, confirmed by angiography, have been published to date. In particular, relatively little information is available on postobliteration, timerelated changes in nidus enhancement, contrast enhancement on CT scan, and gadolinium enhancement on MRI. Several animal experiments in which radiosurgery-induced changes within the irradiated normal brain are analyzed using postcontrast CT scan and/or postgadolinium MRI have been reported [3,19,25]. In these experiments, however, neuroimaging follow-up studies were discontinued within 63 postradiosurgical weeks. In this study, postobliteration neuroimaging findings following angiographically confirmed nidus obliteration were retrospectively analyzed in 11 AVM patients treated with a gamma knife. Based on the limited number of patients in this series, as well as the histologic findings of the radiosurgically obliterated AVM reported previously [32], we briefly discuss pathologic changes in postobliteration AVMs, which are ongoing for at least 5-6 years after radiosurgery; these observations may resolve the debate, which has presented arguments against radiosurgical AVM treatment, as to whether radiosurgery alone changes the nidus from an angiographically visible to an occult AVM.
MATERIALANDMETHODS PATIENT
POPULATION
Among 30 patients with AVMs treated by means of gamma knife radiosurgery during the period from 1978 to 1992, complete nidus obliteration has thus far been angiographically demonstrated in 20 cases between 1 and 5 years after the radiosurgical treatment. In 11 of these 20 patients, CT, MRI, MR angiography, and conventional angiography were performed more than 1 year after angiographic confirmation of nidus obliteration (Table 1). The patients ranged in age from 9 to 54 years (mean, 23 years) at the time of radiosurgery. There were eight females and three males. The AVM manifested with intracranial hemorrhage in all cases. The location of the nidus was supratentorial in ten cases and in-
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Postobliteration Findings on Computed Tomography nance Angiography (MRA), and Angiography
(CT), Magnetic
INTENSITY
CASE
AGE/ PERIODS CONTRAST T,DENSITY ENHANCEMENT WEIGHTED No. SEX (MO) 1
14/F
13
2
10/F
12
3
30/F
5
6
9/F
19/F
13/F
28/M 47/M 26/M
T2WEIGHTED
Complete obliteration Complete obliteration
_
+ + _ _
HYPE HYPE
Hype
_ _
+ +
Hype HYPOHYPO-
HYPE Hype - hyper-
1s~ - hype
+ + +
_ _
+ + +
Is@* Hyper-* 1so-* 1so-*
++ +++ ++ +
HYPOHYPE- Hypo- HYPE HYPE- -
Hype- - hyperHypoHype Hype - hyperHype - hyper-
_ _ -
+ +++ +++ +++ +++
48 17 12 0 16
1so-* Isc- - hypo-
? +
Hype - iso
Hype- - hyper-
-
++
ISO-
2 + 5
HYP@ Hype-
Hype- - hyperHyper-
-
+++ +
0 14 0 15
kSCF*
HYPOHyPo Hype - iso Hype- - iso
HypoHype Hype Hype
-
+ + + +
0 17
ISO-
44 0 14
ISO-
34 0 14
+
Iso- - hypo-
Is0 IS@
Reso-
MRA OR FLOW t%DOLINRJM ANGlOGRAPHIC VOID ENHANCEMENT FINDINC~~~
HyperHYPOHyPo HYPO-
+ + _
84 4 10 34
::
7 8 9
Imaging (MRI), Magnetic
MRI F’INDMGS
CT FINDINGS
4
Resonance
et al
HYP* HypeHypeHYPE
iso iso isoiso-
No vascular abnormalities No vascular abnormalities
No vascular abnormalities
No vascular abnormalities
No vascular
abnormalities 10
22/F
11
38/F
ISO-*
+ _ ++ +
ISOIS@
*Period (mo; month) between angiographically confirmed
obliteration. *Calcification.
+, contrast
or gadolinium
enhancement;
obliteration
GAMMA KNIFE TREATMENT Nine patients underwent gamma knife radiosurgery at the Karolinska Hospital, Stockholm, one patient (case 10) at the University of Tokyo, Tokyo, and the one remaining patient (case 11) at the Heisei Memorial Hospital, Fujieda. The gamma knife treatment was optimal in 10 cases, the nidus was com-
hyper hyperhyperhyper-
and the examination.
-, negative; ?, equivocal;
fratentorial in the one remaining case. The preradiosurgical nidus volume ranged from 0.15 cm3 to 24.15 cm3, with a median of 1.05 cm3. None of the patients had previously undergone either fractionated external beam radiation or interventional radiology. However, a cerebrospinal fluid shunt operation had been carried out in three cases and a craniotomy in two.
-
BMRA, no vascular
+, slight; + +, moderate;
abnormalities;
angiography,
complete
+ + +, marked.
pletely covered, and 20 gray (Gy) or more was given at the periphery [29]. In the one remaining case (case 7) the nidus could not be completely covered due to its size. The selected target dose given at the periphery was 25 Gy or more in 6 cases, 20-25 Gy in 4, and less than 20 Gy in 1 case. NEUROIMAGING FOLLOW-UP The latency interval from treatment to angiographitally confirmed obliteration of the AVM varied from 9 to 39 months, with a mean of 21 months. Thereafter, CT scan and/or MRI were periodically performed in 10 cases. The period between angiographic confirmation of nidus obliteration and these most recent examinations was 12-84 months (mean, 32 months) and that between gamma knife
Postobliteration
Changes in Gamma Knife-Treated
Case 2. Left vertebral •Btion in the temporal nidus obliteration
AVMs
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angiogram obtained before gamma knife radiosurgery showing an arteriovenous malformalobe (A). Left vertebral angiogram obtained 12 months after irradiation showing complete
(B).
treatment and these most recent examinations was 24-96 months (mean, 51 months). All CT scans (axial, precontrast and postcontrast) and MRI (axial, T,-weighted, T,-weighted, and postcontrast T,weighted; gadolinium-diethylenetriamine pentaacetic acid [Cd-DTPA]) were obtained with a section thickness of 5 mm. In performing MRI, a 1.5-Tesla MR imager (MRT 2OOFX, Toshiba Medical, Tokyo) was used. Imaging parameters for these studies included a repetition time (TR) of 500 msec and an echo time (TE) of 15-20 msec for T,-weighted image, and a TR of 2000 msec and a TE of 80 msec for T,-weighted image. In two patients (cases 1 and 2) who underwent radiosurgical treatment in the early 1980s conventional angiography was repeated 1 year after angiographic confirmation of nidus obliteration. In five cases, threedimensional time-of-flight MR angiography, using the MR imager mentioned above, was performed at some point between 16 and 36 months postobliteration (mean, 23 months). Imaging parameters for these studies included a TR of 35 msec, a TE of 8 msec, a flip angle of 30 degrees, matrix of 256 X 192, and section thickness of 1.6 mm X 32 slices. Two images, a sagittal section and a semicoronal section, were routinely obtained.
RESULTS Table 2 summarizes postobliteration findings on CT scan, MRI, MR angiography, and conventional angiography. Among 10 patients who were assessed by CT, the
obliterated nidus was shown to be isodense in eight, and a mixture of isodense and hypodense areas in the other two. Calcification was identified in four cases, in one (case 2) of whom no calcification had been seen on CT scan before gamma knife treatment (Figures 1 and 2). Among seven cases in whom serial postoperative follow-up CT studies were performed, no postobliteration density changes were observed in six cases. In the one remaining case (case 6) however, remarkable postobliteration density changes were observed, an increase followed by a subsequent decrease, recognizable through the end of the second postobliteration year (Figures 3 and 4). In five of the seven cases, a significant time-related decrease in contrast enhancement was observed 1 to 2 years after angiographically confirmed nidus obliteration. Eight patients were evaluated by MRI. On T,weighted imaging, the nidus was shown to be hypointense in six cases and a mixture of hypointense and isointense areas in the two remaining cases. On T,-weighted imaging, however, nidus intensity was more varied than that on T,-weighted imaging: hyperintense in two, hypointense in two, and a mixture of hyperintense and hypointense areas in the four remaining cases. No flow-signal void was demonstrated in any of these cases. Following gadolinium administration, the nidus was enhanced in seven of the eight cases. In the remaining case, however, remarkable enhancement was observable by the fourth postobliteration month, and thereafter disappeared. In seven cases, serial postobliteration follow-up MRI studies were conducted. No
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Case 2. CT scans obtained before radiosurgical treatment showing equivocal contrast enhancement and no calcification (A: left, precontrast CT scan; right, postcontrast CT scan). CT scans and MRl obtained 84 months after angiographic confirmation of nidus obliteration showing the calcified nidus to be enhanced moderately by contrast material and significantly by gadolinium (IS: from left, precontrast CT scan, postcontrast CT scan, T,-weighted MRI, postgadolinium T,-weighted MRl and T,-weighted MRi).
time-related intensity changes were observed on T,-weighted imaging, though time related intensity increases were observed on TX-weighted imaging in two (cases 6 and 9) of the seven cases (Figures 4 and 6). In only two (cases 3 and 9) of the seven cases, a time-related decrease in gadolinium enhancement was observed following angiographitally confirmed nidus obliteration (Figures 5 and 6). In four cases (cases 2,4, 5, and S), significant gadolinium enhancement persisted 3 years or more (maximum, 7 years) after angiographic confirmation of nidus obliteration (Figures 2 and 4). In seven patients who were evaluated by conventional angiography or MR angiography, the absence of vascular abnormalities was confirmed.
DISCUSSION Radiosurgical treatment can result in AVM obliteration after a 1 to 3-year latency period [1,2,4-8,1012,14,16-l&20,23,26-29,32]. This radiosurgically induced change within an AVM is considered to occur as follows: a beam of ionizing radiation initially injures the endothelial cells of vessels, which in-
duces, as a reparative process, a gradual thickening of connective tissue within the intima. This intimal hypertrophy eventually obstructs the lumina of vessels within the AVM [10,27,32]. We have already reported an autopsy case with an AVM treated by gamma knife radiosurgery, in which postmortem studies following AVM-unrelated death were performed after 2-year angiography had demonstrated complete nidus obliteration [32]. In this case, we observed that many of the AVM vessels had obstructed lumina owing to intimal hypertrophy. It was also noted that some of the vessels had patent lumina as well as persistent and recanalizing vessels, which could not be observed angiographically. We also observed evidence of exudation of albuminous fluid in the nidus. Both patent blood flow and serum exudation could be considered to reflect the increased uptake of contrast material and Gd-DTPA within the treated nidus. Furthermore, the most important finding disclosed by this autopsy case is that reconstructive and destructive processes continue within the radiosurgically thrombosed nidus. In this investigation, we analyzed subsequent changes in the nidus demonstrated by means of
Postobliteration
Changes in Gamma Knife-Treated AVMs
Surg Neurol 1996;45:110-22
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Case
6. (A) Left carotid angiogram obtained before gamma knife radiosurgery showing an arteriovenous malformation in the thalamus. (B) Left carotid angiogram obtained 26 months after irradiation showing complete nidus obliteration.
neurodiagnostic imaging techniques following angiographically confirmed nidus obliteration. Although there are a few exceptional cases, postobliteration CT and MRI findings of the nidus can be summarized as follows: The nidus is isodense or a mixture of isodense and hypodense areas on CT, except for areas of calcification. Postcontrast CT shows enhancement, either remarkable or moderate, within 1 to 2 years after angiographic confirmation of nidus obliteration. This nidus enhancement tends to disappear thereafter. T,-weighted MRI reveals hypointensity and/or isointensity. Although intensity varies on Tzweighted MRI, a hyperintense area tends to appear or to increase in size within the nidus with the passage of time. Significant gadolinium enhancement at the site of the treated nidus, which, along with the absence of flow-signal void, can be considered to suggest complete obliteration [ 23,321, tends to persist
for several years following angiographic mation of nidus obliteration.
confir-
Debate continues as to why significant gadolinium enhancement of the treated nidus on MRI persists even after disappearance of contrast enhancement on CT scan (Figures 2 and 4), since Cd-DTPA diffusion in the setting of a disrupted blood-brain barrier is considered to be similar to that of iodinated contrast media [4]. Nevertheless, image reconstruction and the contrast mechanisms of CT and MRI are quite different. Paramagnetic contrast agents like gadolinium do not specifically produce a signal, but rather act indirectly by changing the intrinsic magnetic properties of protons. Because of the exponential relationship, very small amounts of GdDTPA result in dramatic change in signal intensity [30]. In contrast, small amounts of contrast media produce only slight increases in X-ray attenuation, which is undetectable on routine CT examination. As shown in cases 3, 6, and 9, gadolinium enhancement decreases and may ultimately disappear if the flow of
1 Case 6. CT scans and MRI obtained at the time of angiographic confirmation of nidus obliteration (A), and 12 El months (B), 24 months (C), 36 months (D), and 48 months (E) after obliteration (from left, precontrast CT scan, postcontrast CT scan, T,-weighted MRI, postgadolinium T,-weighted MRI, and T,-weighted MRI). Note: 1. Serial follow-up CT scans show postobliteration nidus changes in density and contrast uptake, an increase followed by a subsequent decrease, through the 24th postobliteration month (A,B,C).2. Significant gadolinium enhancement of the nidus on MU1persisted, though contrast enhancement was unremarkable on CT scan throughout 48 months following obliteration @, E). However, a slight decrease in gadolinium enhancement was observed between 36 and 48 postobliteration months (D, E). 3. A gradual increase in the hyperintense area on T,-weighted MRI was observed (B, C).
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9. (A) Right carotid angiogram obtained during gamma knife radiosurgery showing an arteriovenous la Case malformation in the thalamus. @I)Left carotid angiogram obtained 24 months after irradiation showing complete
nidus obliteration.
Gd-DTPA to the treated nidus is completely stopped due to obliteration of all AVM-related vessels. These results show that radiosurgery-induced changes in the nidus may continue for several years after angiography has demonstrated complete AVM obliteration, although the most remarkable changes have generally occurred by the end of the second radiosurgical year [24,31]. Based on the limited number of patients in this series, as well as the autopsy findings mentioned above, these late changes can be considered to involve further obliteration of the remaining or recanalizing vessels and to reflect an ongoing process from coagulation necrosis to liquefaction necrosis. Relatively early decreases in nidus enhancement on postcontrast CT may be attributable to further obliteration of patent vessels. Increased fluid in the extracellular space can contribute to persistent nidus enhancement by Gd-DTPA and an increase in the hyperintense area demonstrated by T,-weighted MRI (Figures 4 and 6). The two following issues must be taken into consideration in light of these results. First, radiosurgically induced nidus obliteration differs fundamentally from angiographically occult vascular malformation (AOVM), which can also be treated by radiosurgery [ 13,151. Unfortunately, the debate as to whether radiosurgery alone changes the nidus from an angiographically visible to an occult AVM has yet to be resolved. Although AOVM is an active lesion and has the potential to bleed before treatment has been carried out, a nidus that has been obliterated by radiosurgery is undergoing a degen-
erative process, leading to liquefaction necrosis, and, therefore, is considered to have less potential for bleeding. Second, in some cases in which 2- or S-year angiography shows a very small residual nidus, slow though complete obliteration can be expected over several years. Therefore, the second course of gamma knife treatment can be postponed for 5 to 6 years following the initial irradiation. We did, in fact, experience a case of complete obliteration confirmed 5 years after irradiation, despite only partial obliteration at the time of 3-year angiography [10,31]. Recently, Pollock et al [23] also reported a patient, whose nidus was angiographitally shown to be partially obliterated 48 months after treatment, in whom complete obliteration was demonstrated at 65 months. Serial follow-up CT scans in case 6 showed postobliteration density changes, an increase followed by a subsequent decrease, through the end of the second postobliteration year. As is well known, a transiently evident attenuation increase on CT scans can be caused by bleeding or a transient increase in blood flow. This patient presented no symptoms suggesting intracerebral hemorrhage when these examinations were performed 1 year after obliteration, although very mild hemorrhage producing no clinical symptoms is possible. However, corresponding to this attenuation increase, a postcontrast CT scan obtained at the same time showed the nidus to be more enhanced than that obtained at the time of obliteration. Subsequent follow-up examinations demonstrated gradual decreases in contrast enhancement. An increased dis-
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Case 9. CT scans and MRl obtained at the time of angiographic confirmation of obliteration showing the nidus to q * be significantly enhanced by gadolinium, despite minimal contrast enhancement, and a T,-weighted image demonstrating hyperintense edema surrounding the nidus (A:from left, precontrast CT scan, postcontrast CT scan, T,-weighted MRI, and T,-weighted MRI). CT scans and MRI obtained 16 months after angiographic confirmation of nidus obliteration showing equivocal enhancement by gadolinium as well as contrast media, and, on T,-weighted MRI, appearance of a hyperintense area within the formerly shown hypointense area and disappearance of hyperintense areas, indicating the adverse effects of radiation (B: from left, precontrast CT scan, postcontrast CT scan, T,-weighted
MRI, postgadolinium T,-weighted MRI, and T,-weighted MRI).
ruption of the blood-brain barrier may be the most feasible explanation. However, the possibility that there were increases in blood flow within the treated nidus following angiographic confirmation of nidus obliteration still cannot be completely ruled out. The authors would like to thank Shunsuke Kawamoto, M.D., Department of Neurosurgery, University of Tokyo, and Tatsuo Hirai, M.D., Heisei Memorial Hospital, forgamma knife treatment, and Mr. Masato Goto, Department of Radiology, Toda Chuo Hospital, for his collaboration in the MR study. The authors are also very grateful to Bierta E. Barfod, M.D., University of Washington School of Medicine, for her assistance in prooheading the English manuscript. This study was supported by scholarships from the Royal Swedish Academy of Sciences, the Japanese Society for the Promotion of Science, the Japan Private School Promotion Foundation, and the Dr. hoe Okamoto International Exchange Fund.
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nial arteriovenous malformations in childhood and adolescence. Pediatr Neurosci 1989; 15:53-61. radio2. Betti 00, Munari C, Rosler R. Stereotactic surgery with the linear accelerator: treatment of arteriovenous malformations. Neurosurgery 1989; 24:311-21. 3. Blatt DR, Friedman WA, Bova FJ, Theele DP, Mickle JP. Temporal characteristics of radiosurgical lesions in an animal model. J Neurosurg 1994;80:1046-55. Bronen BA, Sze G. Magnetic resonance imaging contrast agents theory and application to the central nervous system. J Neurosurg 1990;73:820-36. Colombo F, Benedetti A, Pozza F, Marchetti C, Chierego G. Linear accelerator radiosurgery of cerebral arteriovenous malformations. Neurosurgery 1989;24:833-40. Fabrikant JI, Frankel KA, Phillips MH, Levy RP. Stereotactic heavy charged-particle Bragg peak radiosurgery for intracranial arteriovenous malformations. In: Edwards MSB, Hoffman HJ, eds. Cerebral vascular diseases in children and adolescents. Baltimore: Williams & Wilkins, 1989;389-409. Y. Stereotactic 7. Fabrikant JI, Lyman JT, Hosobuchi heavy-ion Bragg peak radiosurgery for intracranial vascular disorders: method for treatment of deep
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COMMENTARY
It has always seemed strange to me that there are thousands of patients who have been treated at the Karolinska Institute for a period that exceeds 20 years, and yet we have no factual follow-up on these patients, just suppositions which are turned into facts along with recent reviews of the experience of the past few years. Regarding this particular paper, I believe that it should be published because many of the statements are controversial. First of all, I was pleased to see that the authors admit that only 80% of the small AVMs show com-
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plete angiographic obliteration after a latency period of 2-3 years. This is contrary to the opinion presented by many radiosurgeons, including Steiner and Lunsford, where the obliteration rate is estimated higher. According to them, small AVMs are obliterated in 90%-95% of the cases. 1 was also pleased to see that the authors of this manuscript accept the fact that angiographically confirmed disappearance of the nidus should be the goal in all AVM patients who are treated by radiosurgery. Does the same apply to cavernous malformations, which they say can be treated by radiosurgery? What is the endpoint in terms of these later lesions? In analyzing the materials in this paper, they started out with 30 patients during a period of 4 years. I assume that all these patients had small AVMs. They had angiographically demonstrated that 20 of the 30 patients had complete nidus obliteration. For some reason, they took 11 of the 20 patients and studied the MRI, MRA, and conventional angiograms, more than 1 year after angiographic confirmation. Why they chose 11 rather than all 20 patients is beyond my comprehension. They then present a litany on the effect of radiation as it relates to the volume of the AVM. This use of volumetric analysis is confusing. I think that it is very hard to obtain a volumetric analysis from twodimensional studies. It sends the wrong message. I believe that we should stick to the maximum diameter in terms of analyzing our materials. To get to the meat of the paper, they are basically using MRI, MRA, and CT scan data to show dynamic changes in the AVM in response to radiosurgery and not using it solely to analyze obliteration of the nidus. I feel that we must stick to the gold standard of using angiography to determine if the AVM is obliterated by whatever technique is utilized. The MRI is not infallible and may be misleading, and a CT scan is even worse. There are certain terms that are used regarding the changes that they presume are occurring within the AVM nidus. For example, they indicate that the neuroimaging (MRI and CT) may show dynamic changes for several years after angiographic occlusion of the AVM. They relate the changes to “further obliteration of the remaining or recanalizing vessels.” If vessels are remaining or recanalizing, it would seem to me that they should be recognized on the angiogram. Therefore, their complete obliteration would not be seen on the angiogram. The authors’ explanation for this contrariness is not given in the paper. They also point out the vagaries of AVM obliteration by radiosurgery in mentioning a case in which the AVM was not obliterated in 3 years, but in 5 years. Therefore, how are we to know which cases
Yamamoto et al
will be treated successfully by radiosurgery (20% are not)? At what particular time might we expect obliterations? Furthermore, no mention is made of imaging changes that might suggest radiation damage to the surrounding tissues. We have certainly seen these changes frequently at various periods of time after radiosurgery. Some of these changes are reversible, but unfortunately others are not. Discussion of this aspect of radiosurgery is minimized in the literature and is not addressed in this particular manuscript. Finally, they suggest that cavernous malformations can be treated successfully by radiosurgery. They cite two references: one is a preliminary report, and the other is in press in the Japanese literature. I believe that this is another example of wish fulfillment, whereby a wish is turned into a fact. The literature is replete with references to the radiosurgical treatment of cavernous malformations and is overwhelmingly in favor of not using this treatment, since there is no endpoint to determine success. There has been a higher percentage of radiation damage as it relates to the treatment of cavernous malformations and venous malformations than AVMs, a fact which has been mentioned by Dr. Steiner. In spite of the fallacies of literature supporting radiosurgery (this seems to be a generic problem), they should be published, but they should be taken to task at the same time. Bennett M. Stein, M.D. New York, New York This paper is on neuroimaging in post-gamma knife treatment of AVMs. It shows that the CT and MRl appearances can differ and change over time following nidus obliteration. However, many of their patients had different appearances over time and the conclusions that one can draw from the imaging findings are, in my mind, questionable. Furthermore, the explanations and rationale that the authors give for the varying MRI and CT appearances are speculative in some instances, and far from convincing in others. One particular problem is that the authors state that late changes are considered to reflect further obliteration of the remaining or recanalizing vessels, supposedly an ongoing effect of the radiation; however, are the authors absolutely certain that there was no recanalization of viable AVM nidus? Though there are 11 cases in the study, there are only 3 or 4 cases that were serially followed for a significant period of time. Therefore, the conclusions drawn about long-term follow-up are based
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Changes in Gamma Knife-Treated AVMs
upon a very small number of patients. Any conclusions made would have been more valid if more of their patients had been followed serially for longer periods of time. Also, the stated goal of their introduction is to resolve an ongoing debate about the conversion of an AVM to an occult AVM with radiosurgery; it is not clear that they can make such claims or resolve such a debate, given that not one of their patients was pathologically studied. This is especially true given that none of the long-term follow-ups had angiographic analysis. In addition, all of the patients presented with AVM-related hemorrhage. Nowhere in their explanation of MRI evolution do they mention that some of the changes could be related to hemorrhage and the evolution of blood. Where does this fit into their explanation of MRI findings? The tail end of the “Results” section, in which a description of the MRI changes is given, is convoluted and difficult to make any kind of sense of. The discussion of the physiologic effects of the radiosurgery on an AVM is good and instructive. However, the translation of these known effects into an explanation of the imaging findings is not logical or readily understood, in my opinion. For example, patent blood flow and serum exudation might be considered an explanation, but certainly not a reflection, of increased contrast or gadolinium uptake with a treated nidus. It appears from the authors’ bibliography that the post-gamma knife treatment of AVMs and the appearance on CT and MRI have already been described, so it is not clear to me that the authors have described anything new, at least as far as the early and subacute imaging findings go. Again, the explanations offered for the continued MRI enhancement of these nidi as a reflection of late radiation-induced changes is, in my mind, questionable. Once again, it is not clear that the authors have excluded recanalization of nidus vessels. In particular, figure 4E looks like flow voids to me, and I would wonder what an angiogram of this case would show at 48 months. In the end, I found myself unconvinced after reading this paper that the authors had made a significant contribution, or that their contentions were borne out by the imaging findings. Lawrence E. Ginsberg, M.D.
Houston, Texas Dr. Yamamoto and his colleagues have taken a distinct interest in the definition of the process of AVM obliteration after radiosurgery, its timing, and the
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imaging sequelae that accompany it. They have raised a number of interesting points in prior publications, and these are amplified in the present report. Imaging after successful radiosurgery must define angiography obliteration in order to be absolutely sure of the elimination of risk of AVM hemorrhage. Emerging evidence supports the concept that nidus obliteration, even in the presence of a residual early draining vein, may also be associated with complete or almost complete AVM protection. This may be related to the absence of significant AVM shunting, and the likelihood that over time the AVM itself will completely obliterate. Yamamoto and his associates have studied 11 patients who had successful obliteration of their AVMs confirmed by angiography with a defined latency interval. Subsequent imaging studies were then performed to assess the time course of the associated imaging changes. We support Yamamoto’s concept that the appearance of contrast opacification (in the absence of flow-void signal on MRI scan) is highly correlated with successful complete angiographically defined obliteration. We have also seen other patients who have had persistent evidence of contrast enhancement at the target site after AVM obliteration has been confirmed by angiography. However, in most, patients the contrast enhancement slowly fades over time and is present most commonly on or about the time of AVM obliteration. The reasons for blood-brain barrier breakdown at the target volume are not completely clear, and whether they represent neovascularization into a fibrotic area, or leaky capillaries that subsequently resolve over time, has as yet been unanswerable, primarily because such patients do not undergo histopathologic studies. I believe that this report helps to reassure referring and treating physicians that radiosurgery can be associated with recognizable imaging sequelae, and that such sequelae are often associated with clinical relevance. The absolute causes of these imaging changes await further pathologic and radiobiologic studies. L. Dade Lundsford, M.D.
Pittsburgh, Pennsylvania
The authors provide an interesting neuroimaging study of postobliteration nidus changes in cerebral AVM, which have been treated by gamma knife radiosurgery. In their abstract, the authors state that they intend to discuss the ongoing pathologic changes in postobliteration AVMs that occur for at least 5 to 6 years following radiosurgery. This is a difficult goal to achieve, since no pathologic speci-
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mens were examined in this report. What the authors report are the ongoing radiologic changes in the region of the brain that is exposed to gamma radiation during treatment of small cerebral AVMs. The authors they draw speculative conclusions as to what they radiographic developments represent on a histologic level. It is problematic that none of their “long-term” follow-up patients were studied with cerebral angiography, which would have been useful in determining if some of the MRI findings were related to slow recanalization of the malformation. Without the use of arteriography, it is difficult to assume that no recanalization has occurred. The discussion of the MRI findings in the brain following gamma knife therapy is interesting, but adds very little credence to the sketchy scientific basis for the conclusions drawn. Some of the
radiologic changes seen on MlU scanning over the ensuing years could also be related to resolution of microscopic parenchymal hemorrhages surrounding the vascular malformations. This manuscript nicely demonstrates that illdefined radiologic changes are visualized with MRl scanning and continue years after angiographic obliteration of small AVMs by gamma knife radiosurgery. It is uncertain what these changes represent, and until such time as angiography is performed on truly long-term follow-up, recanalization of the vascular malformation cannot be excluded as a possibility. Thomas A. Kopitnik, Jr., M.D. Duke Samson, M.D.
Dallas, Texas