J Neurosnrg 77:1-8, 1992
Clinical outcome of radiosurgery for cerebral arteriovenous malformations LADISLAU
STEINER,M.D., PH.D., CImISTER LINDQUIST,M.D., PH.D.,
JOHN R. ADLER, M.D., JAMES C. TORNER, PH.D., WAYNE ALVES, PH.D., AND
MELITA
STEINER, M.D.
Department of Neurological Surge(v, University of Virginia, Charlottesville, Virginia, and Department of Neurosurgery, Karolinska Institute, Stockholm, Sweden t,- The clinical outcomes are described for 247 consecutive cases of arteriovenous malformation (AVM) treated with the gamma knife between April, 1970, and December 31, 1983. Headache resolved in 65 (66.3%) of the 98 patients presenting with this symptom and improved in an additional nine (9.2%). Of 59 patients admitted with seizures, 11 (18.6%) became seizure-free without anticonvulsant medication and an additional 30 patients (50.8%) became seizure-free with anticonvuisant medication. Pre-existing neurological deficits improved or totally disappeared following radiosurgery in 56.7% of affected cases. This improvement presumably occurred within the frame of the natural history. The protective effect of the ionizing beams against hemorrhage in incompletely obliterated AVM's is analyzed. To assess the rate of rebleeding, probability estimates were calculated using both the person-year method and the Kaplan-Meier life table. With the person-year method the actual rebleed rate is not too different from the values observed in the natural history of the disease (2% to 3%/yr). Analysis by KaplanMeier life-table estimates demonstrated a risk of nearly 3.7%/yr until 60 months after radiosurgery. Five years following treatment, the life table ends in a plateau which could be interpreted as an indication of decrease in the risk of hemorrhage. However, long fiat regions at the right end of the life table do not imply that the real risk of rebleeding is negligible unless a large number of patients have been followed well into or beyond the flat region. KEY WORDS gamma knife 9 radiosurgery 9 arteriovenous malformation intracranial hemorrhage 9 rebleeding 9 seizure 9 headache "
ADIOSURGERY became possible when the proposal by Leksell ~8of a closed stereotaxic system was realized with the construction of a stereotaxic gamma unit (the "gamma knife").19 Leksell's original idea was to use the narrow gamma beams to replace coagulating electrodes in the treatment of pain, Parkinson's disease, and other movement disorders. The beam geometry of the first gamma knife was designed to create a disc-shaped lesion. This first prototype was supplanted by gamma knife I1, and later by gamma knives III and IV, more appropriate instruments for the treatment ofarteriovenous malformations (AVM's) and tumors. Since 1970, one of the authors (L.S.) has used the gamma knife to treat AVM's and well-delineated tumors of the brain. The aim of this report is twofold: 1) to assess the long-term neurological outcome following radiosurgery in AVM cases; and 2) to study whether radiation in the absence of angiographically proven obliteration of the AVM protects against hemorrhage.
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Clinical Material and Methods
The Gamma Knife All but seven patients in the present series were treated with gamma knife II. This prototype was built for the treatment of AVM's and tumors. It had 179 6~ sources and the beams were collimated by one of three available collimator helmets (4, 8, and 14 mm) to give lesions of an almost spherical shape at the 50% isodose surface. At the beginning of the series, the dose rate of the cobalt was approximately 30 Gy/min, decreasing to a minimum of 10 Gy/min at the end of the series. The steep dose gradients determined by the physical specifications of the gamma knife allowed the use of a high dose in a single session for selective elimination of tumors or AVM's.
Patient Population The patients in this series represent the 247 consecutive cases of AVM's treated by the senior author (L.S.)
1
L. Steiner, et al. ment change in neurological signs or symptoms. In the event that the initial questionnaire was not completed and returned, a second one was mailed along with a reminder. This approach yielded some level of followup information in 239 cases (97%). The eight patients from whom no responses have been received were considered lost to follow-up review. Eleven of the 239 patients for whom follow-up information was available have died and, of the 228 surviving patients, all three questionnaires were completed and returned by 130 (57%). A response was received from only the referring physician in 61 cases (27%). Finally, in 37 instances (16%) the patients or their families returned the completed questionnaire, but their doctor did not. For some patients either a review of the hospital records or an additional letter or telephone call was needed to clarify a confusing answer.
Rebleed Rate During the Latency Period
FIG. 1. A and B: Carotid angiograms before radiosurgery in the lateral (A) and in the frontal (B) projections show an arteriovenous malformation (AVM) in the left basal ganglia. C and D: Two years after radiosurgery, lateral (C) and frontal (D) projections confirm that the malformation is obliterated.
prior to January 1, 1984. There were 132 males and 115 females. These patients were a carefully selected population drawn from 23 countries, who were referred largely because they were considered poor candidates for either microsurgical resection or embolization. The location of the AVM's in these patients included both supra- and infratentorial sites with many involving deep brain structures or the brain stem; six patients had a dural component to the AVM. Four patients had two malformations present, one of which was a venous malformation; both AVM's were treated in only two of these cases. Eight patients had undergone previous surgery, either directed at the malformation itself or as an emergency procedure for evacuation of a hematoma. Of the 247 patients, 233 (94%) suffered at least one intracerebral hemorrhage prior to treatment. In contrast, epilepsy was the presenting symptom in only 10 (4%) of the cases.
Neurological Follow- Up Examination To evaluate the neurological outcome in this series, a detailed questionnaire was translated into six languages and a copy was sent to all patients, their families, and the referring neurosurgeons or neurologists. The form was specifically designed to assess any posttreat-
2
The principal aim of radiosurgical treatment is to prevent intracranial bleeding. This can be accomplished by obliterating the AVM. We have no record of a patient sustaining a hemorrhage once it has been angiographically proved that the malformation was obliterated. However, obliteration is not an instantaneous effect of radiosurgery, and in an occasional patient the AVM can remain patent for several years after treatment. During this latency period between treatment and total obliteration of the AVM the patient is at risk of hemorrhage. It has been contended that protection against rebleeding can be conferred without AVM obliteration. J6.~7To produce such an effect, the minimum dose of radiation that the entire malformation had to receive was stated to be 10 Gy (as opposed to doses > 25 Gy, which we have empirically defined as optimum). Furthermore, the protection afforded to nonobliterated AVM's against rebleeding appeared to be a delayed phenomenon requiring up to a 2-year "incubation period" before completion. During this interval a patient remains at risk for rebleeding, but after this time it has been stated that there was nearly complete protection against recurrent hemorrhage. We tested this contention in our study. Because of our follow-up system, the total number of recurrent hemorrhages in this series is known with considerable confidence. However, a precise calculation of the rate of rebleeding before AVM obliteration among patients known to have occluded AVM's requires exact dates for their obliteration. This is, of course, impossible. Furthermore, even rough estimates are difficult because, for sundry reasons, some patients experience very long intervals between follow-up angiograms, and in these cases any approximation of elapsed time until obliteration would be very inaccurate. Therefore, we have chosen to determine indirectly the rate of recurrent hemorrhage by bracketing this value between the highest and lowest possible numbers. For this calculation, the rate of recurrent hemorrhage is first determined assuming that all malformations are
J. Neurosurg./Volume 77~July, 1992
Outcome of radiosurgery for arteriovenous malformations obliterated until established otherwise by angiography. Following this determination the same value is recalculated with the opposite assumption: all AVM's are assumed patent unless demonstrated otherwise. These two methods of calculation yield both the highest and lowest possible rebleeding rates, respectively. Thus, probability estimates were calculated using two methods: 1) the person-year method, which calculates the risk on the total period of follow-up study as related above; and 2) the Kaplan-Meier 15 life-table method, which calculates the risk based on the time elapsed to the event. The person-year method extrapolates the risk to intermediate intervals and assumes a constant risk, while the life-table method is sensitive to the time of each event and is based on the total number of patients remaining at risk at that point. Results
Angiographic Outcome Following Treatment Figure 1 shows angiograms obtained before and after in a typical patient treatment. The incidence of total obliteration of the AVM was 81% of the series. It is not our purpose, however, to report on the angiographic outcome of surgery. Risk of Hemorrhage in the Latency Period Using the patient criteria outlined above, we identified 85 cases in which the AVM was angiographically shown to be patent more than 2 years following treatment. It could be established from the isodose curves that in every instance the whole malformation received at least 10 Gy of radiation. This group of patients carried in total 134 person-years of theoretical risk of hemorrhage. The time encompasses the cumulative interval from the end of the incubation period (24 months) to the date of the last angiogram demonstrating patency. A total of nine hemorrhages occurred throughout that period, a calculated bleed rate of 6.5%/yr. The bias in this determination is that both the number of patients at risk and the length of time the AVM remained patent after treatment are underestimated, and therefore the rate of rebleed may be overestimated. If we recalculate this same value assuming that all treated
FIG. 2. Graph showing rate of rebleeding in nonobliterated arteriovenous malformations (AVM's). Curves show the percent probability of rebleeding following treatment of patients where the AVM received radiation of at least 10 Gy. Cases of rebleeding in the incubation period of obliteration (prior to 24 months) are excluded. The Kaplan-Meier life-table estimates are calculated based on time to bleeding, and the person-year estimates are calculated by the number of events per overall follow-up times.
AVM's remained open until December 31, 1988, the total risk period is 478 years. This method would yield a risk of 1.9%/yr. This latter form of the analysis may overstate the protective effect. Analysis by Kaplan-Meier life-table estimates demonstrated a risk of nearly 3.7%/yr until 60 months after radiosurgery, when the last bleed occurred. The overall risk was 3.4% at 35 months, 7.2% at 48 months, and 11.2% at 60 months. The upper and lower bounds of the 95% confidence interval at 60 months were 4% to 18%, respectively (Fig. 2).
Neurological Symptoms Before Radiosurgery The most frequent neurological symptoms present before radiosurgery were chronic headache, motor function abnormalities, and epilepsy. Of the 228 patients for whom the follow-up study was complete, 98 (42.9%) complained of chronic headache pain prior to irradiation (Table 1). This was followed in frequency by 74 patients (32.5%) presenting with motor deficits and 59 patients (25.9%) who had seizures at some time during the course of their disease. Sensory deficits (20.2%),
TABLE 1 Neurological outcomefollowing radiosurgery in 228 casesof arteriovenous malformation Patient Outcome Pretreatment Signs & Symptoms chronic headache motordeficit seizures sensorydeficit memorydisturbance languagedysfunction
Incidence No. 98 74 59 46 44 35
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% 42.9 32.5 25.9 20.2 19.3 15.4
Completely Resolved No. 65 40 11 19 17 21
% 66.3 54.0 18.6 41.3 38.6 60.0
Significantly Resolved No. 9 13 30 0 6 5
% 9.2 17.6 50.8 0.0 13.6 14.3
No Change No. 24 21 18 27 21 9
% 24.5 28.4 30.5 58.7 47.7 25.7
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L. Steiner, et al. 1). Four patients incurred new sensory deficits after radiosurgery; in three cases these were caused by a rebleed, radiation necrosis, and a stroke occurring at the time of follow-up angiography, respectively. The fourth case involved both a hemifacial hypesthesia and a trace diplopia which developed after radiosurgical treatment of an AVM in the region of the quadrigeminal plate. Contrast-enhanced computerized tomography (CT) did not reveal radiation-induced changes.
FIG. 3. Upper:Pie graphs showing the number of patients with headache before (left) and after (right) radiosurgery.The stripedfield denotes patients with improvement after treatment, the stippledfield denotes unimproved patients, and the open field illustrates the patients without headache. Lower: Pie graphs showing the number of patients with seizure disorder before (left) and after (right) radiosurgery. The striped field denotes patients with complete seizure control on medication, the stippled field denotes patients unchanged after treatment, and the openfield denotes cases without seizures and no medication. Eleven patients developed seizures after treatment.
memory disturbances (19.3%), and speech disorders (15.4%) occurred with less frequency (Table 1).
Outcome Following Radiosurgery In 69% of patients who presented with headaches, motor deficits, seizures, or language or memory deficits, these symptoms were completely resolved or significantly improved following radiosurgery. Headache. Of the 98 patients with chronic headache on admission, this symptom disappeared entirely in 65 patients (66.3%) and was significantly improved in nine cases (9.2%) (Fig. 3 upper and Table 1). Seizures. Of the 59 patients presenting with epilepsy, 41 (69.4%) became seizure-free or were significantly improved after radiosurgery (Fig. 3 lower and Table 1). In contrast, 11 patients developed new seizure disorders following the treatment. Language Dysfunction. Following radiosurgery, speech disorders resolved fully in 21 (60%) of the 35 patients presenting with language dysfunction and were significantly improved in another five cases (14.3%) (Table 1). Motor Deficits. Of the 74 patients presenting with motor deficits, 40 (54%) had complete resolution of their symptoms and 13 (17.6%) were significantly improved (Table 1). Sensory Deficits. Subsequent to radiosurgery, 19 (41.3%) of 46 patients recovered sensation in previously hypesthetic areas, but the remaining 27 patients (58.7 %) showed no improvement of their sensory deficit (Table
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Memory Disturbances. Of 44 cases with memory disturbance on admission, some degree of permanent amnesia was still present in 21 (47.7%) (Table 1). Ten patients reported the onset of memory problems after radiosurgery, four of which were minor. In two cases the problem was caused by a rebleed. In only one of the 10 patients was the memory problem serious enough to warrant formal psychological testing, and the results of these tests were normal. In no patient with a memory problem of obscure origin was there any etiological evidence of radiation-induced changes in the brain. Furthermore, all but two of these patients (one of whom is retired) stated that their working capacity was unimpaired and they were employed. This series included 22 children under the age of 12 years. Despite initial concerns about the effects of radiation in this age group, no patient, family, or doctor reported any mental impairment as a result of therapy and each of these children is reported to have normal intellectual function. The youngest patient treated in this series was 5 years old. Other Neurological Symptoms. Ten patients developed diplopia at the time of their original AVM hemorrhage; in six of these, extraocular movements were normal at the time of follow-up study but, in the other four, diplopia persisted. There were two cases of vertigo and three of dysarthria; these problems dated from an earlier AVM hemorrhage and failed to improve either before or subsequent to the radiosurgical treatment. Cerebellar signs were in every instance the result of a previous hemorrhage. In one patient a slightly unsteady gait developed after the treatment, following a small rebleed during the period between treatment and the time of obliteration of the AVM. One patient whose dural AVM manifested itself as pulsating exophthalmos had total resolution of this problem after the malformation was radiosurgically obliterated. In a patient with a thalamic AVM, an extrapyramidal movement disorder persists unabated despite therapy. Radiosurgery-Induced Deficits. Radiation-induced damage was the cause of deterioration in five of the eight patients who developed new motor deficits. Hemiparesis ranging from slight to moderate occurred in four of these cases; the fifth had foot drop. Sensory deficit was caused by radiosurgery in one case. Six patients in this series had fixed homonymous hemianopsia as a result of an earlier hemorrhage. An additional four patients developed a homonymous hemianopsia after the treatment. In three cases there J. Neurosurg. / Volume 77~July, 1992
Outcome of radiosurgery for arteriovenous malformations was a direct cause-effect relationship between radiosurgery and the symptom; an angiogram in one patient revealed possible narrowing of a number of small arteries on the medial surface of the occipital lobe, and an incongruous homonymous hemianopsia in another patient is suspected of representing radiation injury to the optic tract. There were, however, no CT findings typical of radiation-induced changes in the brain tissue. A complication at angiography resulting in a posterior cerebral artery stroke was the cause of the field cut in the fourth case. Functional Recovery. A full working capacity was reported in 162 (71.1%) of the 228 patients at the time of follow-up contact (Table 2). In 35 patients (21.6%) this represented an improvement over their condition prior to radiosurgery. The remaining 67 patients (29.6%) were thought to be occupationally handicapped at some level. In this group, 35 were partially disabled both before and after radiosurgery; however, in 15 instances a patient's working capacity increased from "not at all" to "partial." Seventeen patients were listed as totally disabled both prior to and following treatment. Eight patients who had a normal working capacity before treatment described themselves as occupationally handicapped at the time of the follow-up contact. This deterioration was a result of AVM rebleeding in three cases and radiation-induced damage in two other instances. Severe depression was the cause of disability in one patient, while another case involved a young man who suffers from chronic epilepsy. Employment. A total of 158 patients (69.3%) were either employed or functioning at a satisfactory level as students or housewives (11 cases) both prior to and after radiosurgery (Table 2). Another 42 patients were unable to work either before or after their treatment; however, five of these are retired and one is a man with chronic renal failure who has been receiving permanent disability payments. In 16 instances, patients who were previously unemployed are now working. Meanwhile, 12 patients who were working at the time of radiosurgery are currently not doing so. In this last group is a man whose working capacity deteriorated because of a rebleed. Additionally, there are four older patients who retired after their treatment and a young man who sustained an arm injury and is now unemployable. The circumstances surrounding the loss of employment in the remaining cases are not known. Sexual Function. The answers to an inquiry into sexual function are heavily influenced both by each patient's system of values and his or her age. Despite these limitations, the answers to this question can reflect some measure of general well-being. Given these provisos, 185 patients (81.1%) reported having normal agerelated sexual function both prior to and after radiosurgery (Table 2). This group includes children who largely because of their age, may not have been sexually active. Sexual activity was reduced or absent before treatment J. Neurosurg. / Volume 77~July, 1992
TABLE 2 Functional recoveryfollowing radiosurgery in 228 patients Cases
Functional Recovery Level occupational capacity full capacity same as before surgery improved following surgery occupationally handicapped partial before & after improved from no capacity total before & after actual employment employed before & after employed after not employed after unable before & after sexual function normal before & after improved after reduced after reduced or absent before & after
No.
Percent
162 127 35 67 35 15 17
71.1 78.4 21.6 29.6 53.0 22.7 24.3
158 16 12 42
69.3 7.0 5.3 18.4
185 21 9 13
81.1 9.2 3.9 5.7
and at the time of follow-up review in another 13 patients. In 21 cases there was an improvement in sexual function between the time of radiosurgery and follow-up data acquisition, while nine patients reported a decline in sexual function. This response was not related to any new neurological deficits and was prompted more commonly by the death of a spouse or by age-dependent psychological changes (Table 2). Mortality. As of May 1, 1986, 11 of the 239 patients for whom follow-up information was available had died. Recurrent hemorrhage was the cause of death in five patients and one patient committed suicide because of intractable pain syndrome originating with his initial AVM rupture. The causes of death in the remaining five patients were unrelated to the AVM or to radiosurgery. Discussion Radiosurgery is an effective method for the treatment of AVM. The gamma knife radiosurgical procedure for AVM has been described previously. 18"31'33"34"38"39 The results obtained were good in terms of both total obliteration of AVM and an overall functional outcome, and are comparable with the best published results of microsurgery, especially those series involving poorly accessible AVM's. 5-7"12-14'22'23'25'28-30'41-43
Referral Bias Relative to other series of AVM's our study includes an unusually high incidence of ruptured lesions (94%) and a corresponding small number of seizures as initial symptoms. This predominance of hemorrhagic presentation most likely reflects a referral bias. Angiographic Outcome Angiographic results of radiosurgical treatment of 5
L. Steiner, et al. AVM's have been extensively reported by Steiner, et al. 20'36'38-40 At the different follow-up stages of our material between 1977 and 1991, the cumulative incidence of total obliteration of AVM's varied between 79% and 95%. 20`35-40 Neurological Outcome The present report focuses on posttreatment neurological outcome and rebleeding. Many patients have experienced total or nearly total resolution of preexisting neurological deficits after radiosurgery. Improvement in the neurological condition of patients treated by radiosurgery may occur in the natural course of the disease, so caution is called for when evaluating amelioration of neurological deficits. Although most gains in neurological function seem attributable to the post-hemorrhage recovery process, it is still plausible that vascular steal was responsible for a few patients' symptoms. In such cases, neurological deficits could potentially improve if radiosurgical treatment would lead to either total or near total obliteration of the AVM. Headache. The disappearance of headache could often be correlated with AVM obliteration. This association was not absolute, however, and in several patients headaches persisted after complete AVM obliteration. Seizures. Seizure was the presenting symptom in 59 of the 247 patients in this series. Radiosurgery resulted in cessation of seizures, with or without anticonvulsant drugs, in 41 of these patients. Resolution of the seizure disorders was confounded by the fact that anticonvulsant medications were started or drug levels optimized in several cases at the time of or shortly after radiosurgery. Nevertheless, 11 patients who had chronic epilepsy and took medication prior to radiosurgery became seizure-free and could stop their anticonvulsant drugs. In three of these cases, this apparent "cure" of epilepsy occurred without obliteration of the AVM. From this observation one may speculate that the radiosurgical treatment had a direct effect on the epileptic neurons, ameliorating the seizure condition. Observations of Elomaa, 8'9 Barcia-Salorio, et al., L2 and Rossi, et aL, 27 support these assumptions. Further studies continue to clarify this hypothesis. There were 11 patients with new seizures. Concerning these cases, it should be remembered that all had suffered intracerebral hemorrhages before treatment, with extensive brain tissue damage in some. Protection Against Rebleeding Following Radiosurgery The contention that protection against rebleeding can be conferred without AVM obliteration ~6'~7is at odds with the consensus among neurosurgeons (shared by the authors) that patients remain at risk for rebleeding as long as the malformation is still patent, whether treated by microsurgery, radiosurgery, or endovascular techniques. The rebleed rates in irradiated but nonob6
literated AVM's suggest that radiation itself is not protective against subsequent rupture. This is particularly apparent with the person-year assessment method, which calculates the risk on the total follow-up period. The actual rebleed rate must lie somewhere between 1.9% and 6.5% which is not very dissimilar to the typical values reported for untreated AVM's of between 2% and 3%~yr. 3,4,t~ However, the answer is less clearcut with the Kaplan-Meier life-table method, which calculates the risk based on the time of followup study prior to the hemorrhagic events. According to the life-table estimates, radiosurgery does not appear to confer any significant protection against rebleeding in the nonobliterated AVM in the first 5 years following treatment. However, after this period the life table ends in a plateau which could be interpreted as an indication of a sustained decrease in the risk of hemorrhage late in the follow-up period (Fig. 2). There are serious arguments against such a conclusion. Peto, et al., 26 contend that any conclusion based on the fine detail of such a graph (life table) is likely to be wrong. According to them, particularly long fiat regions at the right end of the life table do not imply that the real risk of death (or other events such as bleeding) among patients who are still alive is negligible, unless a large number of patients have observation times well into or beyond the fiat regions. Our analysis of hemorrhage with a life table falls short of being conclusive because of the relatively small number of patients at risk for bleeds in the late follow-up period. It is important to note that the premise of Peto, et al., is referenced to an example comprising 102 patients. In focusing on finer details of the life table for hemorrhage in our patients with nonobliterated AVM's, the imprecision of estimates in the late follow-up period precludes strong conclusions regarding the plateau. The true risk of hemorrhage at 60 months is likely (p = 0.95) to be between 4% and 18% (rounded to the nearest integer). Moreover, the upper bound of the 95 % confidence interval for hemorrhage at the end of the observation period is not higher than 18%. In fact, it is probably lower than 18% due to losses from the followup group. This 18% to 20% rate at 96 months is a possible, albeit improbable, value for hemorrhage at the end of the observation period and is consistent with a risk that is constant over the entire follow-up period. Although according to Peto, et al., 26 the plateau at the right end of the life curve is not pertinent, it is difficult to ignore in practice. Actually, based on a Poisson model of risk, a rate for hemorrhage as high as 1.2%/yr would yield confidence limits including 0. To be sure, a lower rate might be explained by the fact that the majority of the AVM's under scrutiny may have been obliterated and thus the number of individuals at risk for bleeding was lower. Indeed, it cannot be totally excluded that additional cure might have occurred and was not discovered between the time of the last anglogram and completion of the follow-up period (December 31, 1988). Furthermore, the possibility of inadeJ. Neurosurg. / Volume 77~July, 1992
Outcome of radiosurgery for arteriovenous malformations quate assessment by the referring physician or failure of the patient to see a physician if the symptoms were discrete should not be dismissed. In spite of strong evidence to the contrary, the contention that radiosurgery does confer protection against rebleeding in a still-patent AVM may have major influence on the thinking of physicians involved in the management of these patients. Therefore, the pertinence of information provided by the life-curve method should be studied carefully in a large series of patients with long follow-up intervals.
Conclusions Radiosurgery induces a high incidence o f angiographically proven obliteration of A V M ' s with a relatively low incidence of undue side effects. Although there is a suggestion of improvement in pretreatment symptoms, any relation with the treatment still remains to be proved. We believe that protection against rebleeding occurs only if the AVM is totally obliterated. Nevertheless, since the life-curve method suggests incongruities in this respect, the problem should be further investigated in large series of patients observed over a long period of time.
Acknowledgments We wish to express our warm thanks to Drs. John G. Ferguson and Ralph F. Frankowski for their valuable suggestions in interpreting the life-table findings. We thank also Mrs. Lucille Staiger, Mrs. Ruth Clawson, and Mrs. Terri Moulton who assisted in the preparation of the manuscript and illustrations.
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Neurosurg 37:562-570, 1972 11. Fults D, Kelly DL Jr: Natural history of arteriovenous malformations of the brain: a clinical study. Neurosurgery 15:658-662, 1984 12. Gamache F, Patterson R: Infratentorial arteriovenous malformations, in Fein J, Flamm ES (eds): Cerehrovascular Surgery. New York: Springer-Verlag, 1985, Vol IV, pp 1117-1137 13. Graf CJ, Perret GE, Torner JC: Bleeding from cerebral arteriovenous malformations as part of their natural history. J Nenrosurg 58:331-337, 1983 14. Heros RC, Korosue K, Diebold PM: Surgical excisions of cerebral arteriovenous malformations: late results. Neurosurgery 26:570-578, 1990 15. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Slat Assoe 53:457-481, 1958 16. Kjellberg RN: Proton beam therapy for arteriovenous malformations of the brain, in Schmidek HH, Sweet WH (eds): Operative Neurosurgical Techniques. Indications, Methods, and Results, ed 2. New York: Grune & Stratton, 1988, pp 911-915 17. Kjellberg RN, Abe M: Stereotactic Bragg peak proton beam therapy, in Lunsford LD (ed): Modern Stereotactic Neurosurgery. Boston: Martinus Nijhoff, 1988, pp 463-470 18. Leksell L: The stereotaxic method of radiosurgery of the brain. Acta Chir Scand 102:316-319, 1951 19. Leksell L: Stereotaxis and Radiosurgery. An Operative System. Springfield, Ill: Charles C Thomas, 1971, pp 1-66 20. Lindquist C, Steiner L: Stereotactic radiosurgical treatment of malformations of the brain, in Lunsford LD (ed): Modern Stereotactic Neurosurgery. Boston: Martinus Nijhoff, 1988, pp 491-506 21. Luessenhop AJ: Natural history of cerebral arteriovenous malformations, in Wilson CB, Stein BM (eds): lntracranial Arteriovenous Malformations. Baltimore: Williams & Wilkins, 1984, pp 12-23 22. Malik GM, Umanski F, Patel S, et al: Microsurgical removal of arteriovenous malformations of the basal ganglia. Neurosurgery 23:209-217, 1988 23. Martin NA, Wilson CB: Medial occipital arteriovenous malformations. Surgical treatment. J Neurosurg 56: 798-802, 1982 24. Ondra SL, Troupp H, George ED, et al: The natural history of symptomatic arteriovenous malformations of the brain: a 24-year follow-up assessment. J Nenrosurg 73:387-391, 1990 25. Parkinson D, Bachers G: Arteriovenous malformations. Summary of 1130consecutive supratentorial cases. J Neurosnrg 53:285-299, 1980 26. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Br J Cancer 34:585-612, 1976 27. Rossi GF, Scerrati M, Roselli R: Epileptogenic cerebral low-grade tumors: effect of interstitial stereotaclic irradiation on seizures. Appl Neurophysiol 16:127-132, 1985 28. Solomon RA, Stein BM: Management of arteriovenous malformations of the brain stem. J Neurosurg 64: 857-864, 1986 29. Spetzler RF, Martin NA, Carter LP, etal: Surgical management of large AVM's by staged embolization and operative excision. J Neurosurg 67:17-28, 1987 30. Stein BM: Arteriovenous malformations of the medial cerebral hemisphere and the limbic system. J Neorosurg 60:23-31, 1984
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L. Steiner, et al. 31. Steiner L: Radiosurgery in cerebral arteriovenous malformations, in Fein JM, Harem ES (eds): Cerebrovascular Surgery. New York: Springer-Verlag, 1985, Vol IV, pp 1161-1215 32. Steiner L: Stereotactic radiosurgery with the cobalt 60 gamma unit in the surgical treatment of intracranial tumors and arteriovenous malformations, in Schmidek HH, Sweet WH (eds): Operative Neurosurgical Techniques. Indications, Methods, and Results, ed 2. New York: Grune & Stratton, 1988, pp 515-529 33. Steiner L: Treatment of arteriovenous malformations by radiosurgery, in Wilson CB, Stein BM (eds): Intraeranial Arteriovenous Malformations. Baltimore: Williams & Wilkins, 1984, pp 295-313 34. Steiner L, Greitz T, Backlund EO, et al: Radiosurgery in arterio-venous malformations of the brain, in Szikla G (ed): Stereotaetic Cerebral Irradiation. Amsterdam: Elsevier, 1979, pp 257-269 35. Steiner L, Greitz T, Leksell L, et al: Radiosurgery in intracranial arteriovenous malformations. II. A follow-up study, in Carrea R, Le Vay D (eds): Neurological Surgery with Emphasis on Non-Invasive Methods of Diagnosis and Treatment: Proceedings of the 6th International Congress of Neurological Surgeons. Amsterdam: Excerpta Medica, 1977, pp 168-180 36. Steiner L, Leksell L, Forster DMC, et al: Stereotactic radiosurgery in intracranial arterio-venous malformations. Aeta Neuroehir 21 (Suppl):195-209, 1974 37. Steiner L, Leksell L, Greitz T, et al: Stereotaxic radiosurgery for cerebral arteriovenous malformations. Report of a case. Acta Chir Stand 138:459-464, 1972
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38. Steiner L, Lindquist C: Radiosurgery in cerebral arteriovenous malformation. Neurosurg State Art Rev 2: 329-335, 1987 39. Steiner L, Lindquist C, Steiner M: Radiosurgery. Adv Teeh Stand Neurosurg 19 (In press) 40. Steiner L, Lindquist C, Steiner M: Radiosurgery with focused gamma-beam irradiation in children, in Edwards SB, Hoffman HJ (eds): Cerebral Vascular Disease in Children and Adolescents. Baltimore: Williams & Wilkins, 1989, pp 367-388 41. Wilson CB, U HS, Domingue J: Microsurgical treatment of intracranial vascular malformations. J Neurosurg 51: 446-454, 1979 42. Yamada S, Brauer FS, Knierim DS: Direct approach to arteriovenous malformations in functional areas of the cerebral hemisphere. J Neurosurg 72:418-425, 1990 43. Ya~argil MG: Mieroneurosurgery, Vol III B: AVM of the Brain. New York: George Thieme, 1988
Manuscript received February 15, 1991. Accepted in final form December 17, 1991. Address for Dr. Adler: Department of Neurosurgery, Stanford Medical Center, Stanford, California. Address for Dr. Torner: Department of Preventive Medicine and Environmental Health, University of Iowa, Iowa City, Iowa. Address reprint requests to: Ladislau Steiner, M.D., Ph.D., Department of Neurological Surgery, University of Virginia, Health Sciences Center, Box 212, Charlottesville, Virginia 22908.
J. Neurosurg. / Volume 77~July, 1992
Clinical outcome of radiosurgery for cerebral arteriovenous malformations LADISLAU
STEINER,M.D., PH.D., CImISTER LINDQUIST,M.D., PH.D.,
JOHN R. ADLER, M.D., JAMES C. TORNER, PH.D., WAYNE ALVES, PH.D., AND
MELITA
STEINER, M.D.
Department of Neurological Surge(v, University of Virginia, Charlottesville, Virginia, and Department of Neurosurgery, Karolinska Institute, Stockholm, Sweden t,- The clinical outcomes are described for 247 consecutive cases of arteriovenous malformation (AVM) treated with the gamma knife between April, 1970, and December 31, 1983. Headache resolved in 65 (66.3%) of the 98 patients presenting with this symptom and improved in an additional nine (9.2%). Of 59 patients admitted with seizures, 11 (18.6%) became seizure-free without anticonvulsant medication and an additional 30 patients (50.8%) became seizure-free with anticonvuisant medication. Pre-existing neurological deficits improved or totally disappeared following radiosurgery in 56.7% of affected cases. This improvement presumably occurred within the frame of the natural history. The protective effect of the ionizing beams against hemorrhage in incompletely obliterated AVM's is analyzed. To assess the rate of rebleeding, probability estimates were calculated using both the person-year method and the Kaplan-Meier life table. With the person-year method the actual rebleed rate is not too different from the values observed in the natural history of the disease (2% to 3%/yr). Analysis by KaplanMeier life-table estimates demonstrated a risk of nearly 3.7%/yr until 60 months after radiosurgery. Five years following treatment, the life table ends in a plateau which could be interpreted as an indication of decrease in the risk of hemorrhage. However, long fiat regions at the right end of the life table do not imply that the real risk of rebleeding is negligible unless a large number of patients have been followed well into or beyond the flat region. KEY WORDS gamma knife 9 radiosurgery 9 arteriovenous malformation intracranial hemorrhage 9 rebleeding 9 seizure 9 headache "
ADIOSURGERY became possible when the proposal by Leksell ~8of a closed stereotaxic system was realized with the construction of a stereotaxic gamma unit (the "gamma knife").19 Leksell's original idea was to use the narrow gamma beams to replace coagulating electrodes in the treatment of pain, Parkinson's disease, and other movement disorders. The beam geometry of the first gamma knife was designed to create a disc-shaped lesion. This first prototype was supplanted by gamma knife I1, and later by gamma knives III and IV, more appropriate instruments for the treatment ofarteriovenous malformations (AVM's) and tumors. Since 1970, one of the authors (L.S.) has used the gamma knife to treat AVM's and well-delineated tumors of the brain. The aim of this report is twofold: 1) to assess the long-term neurological outcome following radiosurgery in AVM cases; and 2) to study whether radiation in the absence of angiographically proven obliteration of the AVM protects against hemorrhage.
R
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9
Clinical Material and Methods
The Gamma Knife All but seven patients in the present series were treated with gamma knife II. This prototype was built for the treatment of AVM's and tumors. It had 179 6~ sources and the beams were collimated by one of three available collimator helmets (4, 8, and 14 mm) to give lesions of an almost spherical shape at the 50% isodose surface. At the beginning of the series, the dose rate of the cobalt was approximately 30 Gy/min, decreasing to a minimum of 10 Gy/min at the end of the series. The steep dose gradients determined by the physical specifications of the gamma knife allowed the use of a high dose in a single session for selective elimination of tumors or AVM's.
Patient Population The patients in this series represent the 247 consecutive cases of AVM's treated by the senior author (L.S.)
1
L. Steiner, et al. ment change in neurological signs or symptoms. In the event that the initial questionnaire was not completed and returned, a second one was mailed along with a reminder. This approach yielded some level of followup information in 239 cases (97%). The eight patients from whom no responses have been received were considered lost to follow-up review. Eleven of the 239 patients for whom follow-up information was available have died and, of the 228 surviving patients, all three questionnaires were completed and returned by 130 (57%). A response was received from only the referring physician in 61 cases (27%). Finally, in 37 instances (16%) the patients or their families returned the completed questionnaire, but their doctor did not. For some patients either a review of the hospital records or an additional letter or telephone call was needed to clarify a confusing answer.
Rebleed Rate During the Latency Period
FIG. 1. A and B: Carotid angiograms before radiosurgery in the lateral (A) and in the frontal (B) projections show an arteriovenous malformation (AVM) in the left basal ganglia. C and D: Two years after radiosurgery, lateral (C) and frontal (D) projections confirm that the malformation is obliterated.
prior to January 1, 1984. There were 132 males and 115 females. These patients were a carefully selected population drawn from 23 countries, who were referred largely because they were considered poor candidates for either microsurgical resection or embolization. The location of the AVM's in these patients included both supra- and infratentorial sites with many involving deep brain structures or the brain stem; six patients had a dural component to the AVM. Four patients had two malformations present, one of which was a venous malformation; both AVM's were treated in only two of these cases. Eight patients had undergone previous surgery, either directed at the malformation itself or as an emergency procedure for evacuation of a hematoma. Of the 247 patients, 233 (94%) suffered at least one intracerebral hemorrhage prior to treatment. In contrast, epilepsy was the presenting symptom in only 10 (4%) of the cases.
Neurological Follow- Up Examination To evaluate the neurological outcome in this series, a detailed questionnaire was translated into six languages and a copy was sent to all patients, their families, and the referring neurosurgeons or neurologists. The form was specifically designed to assess any posttreat-
2
The principal aim of radiosurgical treatment is to prevent intracranial bleeding. This can be accomplished by obliterating the AVM. We have no record of a patient sustaining a hemorrhage once it has been angiographically proved that the malformation was obliterated. However, obliteration is not an instantaneous effect of radiosurgery, and in an occasional patient the AVM can remain patent for several years after treatment. During this latency period between treatment and total obliteration of the AVM the patient is at risk of hemorrhage. It has been contended that protection against rebleeding can be conferred without AVM obliteration. J6.~7To produce such an effect, the minimum dose of radiation that the entire malformation had to receive was stated to be 10 Gy (as opposed to doses > 25 Gy, which we have empirically defined as optimum). Furthermore, the protection afforded to nonobliterated AVM's against rebleeding appeared to be a delayed phenomenon requiring up to a 2-year "incubation period" before completion. During this interval a patient remains at risk for rebleeding, but after this time it has been stated that there was nearly complete protection against recurrent hemorrhage. We tested this contention in our study. Because of our follow-up system, the total number of recurrent hemorrhages in this series is known with considerable confidence. However, a precise calculation of the rate of rebleeding before AVM obliteration among patients known to have occluded AVM's requires exact dates for their obliteration. This is, of course, impossible. Furthermore, even rough estimates are difficult because, for sundry reasons, some patients experience very long intervals between follow-up angiograms, and in these cases any approximation of elapsed time until obliteration would be very inaccurate. Therefore, we have chosen to determine indirectly the rate of recurrent hemorrhage by bracketing this value between the highest and lowest possible numbers. For this calculation, the rate of recurrent hemorrhage is first determined assuming that all malformations are
J. Neurosurg./Volume 77~July, 1992
Outcome of radiosurgery for arteriovenous malformations obliterated until established otherwise by angiography. Following this determination the same value is recalculated with the opposite assumption: all AVM's are assumed patent unless demonstrated otherwise. These two methods of calculation yield both the highest and lowest possible rebleeding rates, respectively. Thus, probability estimates were calculated using two methods: 1) the person-year method, which calculates the risk on the total period of follow-up study as related above; and 2) the Kaplan-Meier 15 life-table method, which calculates the risk based on the time elapsed to the event. The person-year method extrapolates the risk to intermediate intervals and assumes a constant risk, while the life-table method is sensitive to the time of each event and is based on the total number of patients remaining at risk at that point. Results
Angiographic Outcome Following Treatment Figure 1 shows angiograms obtained before and after in a typical patient treatment. The incidence of total obliteration of the AVM was 81% of the series. It is not our purpose, however, to report on the angiographic outcome of surgery. Risk of Hemorrhage in the Latency Period Using the patient criteria outlined above, we identified 85 cases in which the AVM was angiographically shown to be patent more than 2 years following treatment. It could be established from the isodose curves that in every instance the whole malformation received at least 10 Gy of radiation. This group of patients carried in total 134 person-years of theoretical risk of hemorrhage. The time encompasses the cumulative interval from the end of the incubation period (24 months) to the date of the last angiogram demonstrating patency. A total of nine hemorrhages occurred throughout that period, a calculated bleed rate of 6.5%/yr. The bias in this determination is that both the number of patients at risk and the length of time the AVM remained patent after treatment are underestimated, and therefore the rate of rebleed may be overestimated. If we recalculate this same value assuming that all treated
FIG. 2. Graph showing rate of rebleeding in nonobliterated arteriovenous malformations (AVM's). Curves show the percent probability of rebleeding following treatment of patients where the AVM received radiation of at least 10 Gy. Cases of rebleeding in the incubation period of obliteration (prior to 24 months) are excluded. The Kaplan-Meier life-table estimates are calculated based on time to bleeding, and the person-year estimates are calculated by the number of events per overall follow-up times.
AVM's remained open until December 31, 1988, the total risk period is 478 years. This method would yield a risk of 1.9%/yr. This latter form of the analysis may overstate the protective effect. Analysis by Kaplan-Meier life-table estimates demonstrated a risk of nearly 3.7%/yr until 60 months after radiosurgery, when the last bleed occurred. The overall risk was 3.4% at 35 months, 7.2% at 48 months, and 11.2% at 60 months. The upper and lower bounds of the 95% confidence interval at 60 months were 4% to 18%, respectively (Fig. 2).
Neurological Symptoms Before Radiosurgery The most frequent neurological symptoms present before radiosurgery were chronic headache, motor function abnormalities, and epilepsy. Of the 228 patients for whom the follow-up study was complete, 98 (42.9%) complained of chronic headache pain prior to irradiation (Table 1). This was followed in frequency by 74 patients (32.5%) presenting with motor deficits and 59 patients (25.9%) who had seizures at some time during the course of their disease. Sensory deficits (20.2%),
TABLE 1 Neurological outcomefollowing radiosurgery in 228 casesof arteriovenous malformation Patient Outcome Pretreatment Signs & Symptoms chronic headache motordeficit seizures sensorydeficit memorydisturbance languagedysfunction
Incidence No. 98 74 59 46 44 35
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% 42.9 32.5 25.9 20.2 19.3 15.4
Completely Resolved No. 65 40 11 19 17 21
% 66.3 54.0 18.6 41.3 38.6 60.0
Significantly Resolved No. 9 13 30 0 6 5
% 9.2 17.6 50.8 0.0 13.6 14.3
No Change No. 24 21 18 27 21 9
% 24.5 28.4 30.5 58.7 47.7 25.7
3
L. Steiner, et al. 1). Four patients incurred new sensory deficits after radiosurgery; in three cases these were caused by a rebleed, radiation necrosis, and a stroke occurring at the time of follow-up angiography, respectively. The fourth case involved both a hemifacial hypesthesia and a trace diplopia which developed after radiosurgical treatment of an AVM in the region of the quadrigeminal plate. Contrast-enhanced computerized tomography (CT) did not reveal radiation-induced changes.
FIG. 3. Upper:Pie graphs showing the number of patients with headache before (left) and after (right) radiosurgery.The stripedfield denotes patients with improvement after treatment, the stippledfield denotes unimproved patients, and the open field illustrates the patients without headache. Lower: Pie graphs showing the number of patients with seizure disorder before (left) and after (right) radiosurgery. The striped field denotes patients with complete seizure control on medication, the stippled field denotes patients unchanged after treatment, and the openfield denotes cases without seizures and no medication. Eleven patients developed seizures after treatment.
memory disturbances (19.3%), and speech disorders (15.4%) occurred with less frequency (Table 1).
Outcome Following Radiosurgery In 69% of patients who presented with headaches, motor deficits, seizures, or language or memory deficits, these symptoms were completely resolved or significantly improved following radiosurgery. Headache. Of the 98 patients with chronic headache on admission, this symptom disappeared entirely in 65 patients (66.3%) and was significantly improved in nine cases (9.2%) (Fig. 3 upper and Table 1). Seizures. Of the 59 patients presenting with epilepsy, 41 (69.4%) became seizure-free or were significantly improved after radiosurgery (Fig. 3 lower and Table 1). In contrast, 11 patients developed new seizure disorders following the treatment. Language Dysfunction. Following radiosurgery, speech disorders resolved fully in 21 (60%) of the 35 patients presenting with language dysfunction and were significantly improved in another five cases (14.3%) (Table 1). Motor Deficits. Of the 74 patients presenting with motor deficits, 40 (54%) had complete resolution of their symptoms and 13 (17.6%) were significantly improved (Table 1). Sensory Deficits. Subsequent to radiosurgery, 19 (41.3%) of 46 patients recovered sensation in previously hypesthetic areas, but the remaining 27 patients (58.7 %) showed no improvement of their sensory deficit (Table
4
Memory Disturbances. Of 44 cases with memory disturbance on admission, some degree of permanent amnesia was still present in 21 (47.7%) (Table 1). Ten patients reported the onset of memory problems after radiosurgery, four of which were minor. In two cases the problem was caused by a rebleed. In only one of the 10 patients was the memory problem serious enough to warrant formal psychological testing, and the results of these tests were normal. In no patient with a memory problem of obscure origin was there any etiological evidence of radiation-induced changes in the brain. Furthermore, all but two of these patients (one of whom is retired) stated that their working capacity was unimpaired and they were employed. This series included 22 children under the age of 12 years. Despite initial concerns about the effects of radiation in this age group, no patient, family, or doctor reported any mental impairment as a result of therapy and each of these children is reported to have normal intellectual function. The youngest patient treated in this series was 5 years old. Other Neurological Symptoms. Ten patients developed diplopia at the time of their original AVM hemorrhage; in six of these, extraocular movements were normal at the time of follow-up study but, in the other four, diplopia persisted. There were two cases of vertigo and three of dysarthria; these problems dated from an earlier AVM hemorrhage and failed to improve either before or subsequent to the radiosurgical treatment. Cerebellar signs were in every instance the result of a previous hemorrhage. In one patient a slightly unsteady gait developed after the treatment, following a small rebleed during the period between treatment and the time of obliteration of the AVM. One patient whose dural AVM manifested itself as pulsating exophthalmos had total resolution of this problem after the malformation was radiosurgically obliterated. In a patient with a thalamic AVM, an extrapyramidal movement disorder persists unabated despite therapy. Radiosurgery-Induced Deficits. Radiation-induced damage was the cause of deterioration in five of the eight patients who developed new motor deficits. Hemiparesis ranging from slight to moderate occurred in four of these cases; the fifth had foot drop. Sensory deficit was caused by radiosurgery in one case. Six patients in this series had fixed homonymous hemianopsia as a result of an earlier hemorrhage. An additional four patients developed a homonymous hemianopsia after the treatment. In three cases there J. Neurosurg. / Volume 77~July, 1992
Outcome of radiosurgery for arteriovenous malformations was a direct cause-effect relationship between radiosurgery and the symptom; an angiogram in one patient revealed possible narrowing of a number of small arteries on the medial surface of the occipital lobe, and an incongruous homonymous hemianopsia in another patient is suspected of representing radiation injury to the optic tract. There were, however, no CT findings typical of radiation-induced changes in the brain tissue. A complication at angiography resulting in a posterior cerebral artery stroke was the cause of the field cut in the fourth case. Functional Recovery. A full working capacity was reported in 162 (71.1%) of the 228 patients at the time of follow-up contact (Table 2). In 35 patients (21.6%) this represented an improvement over their condition prior to radiosurgery. The remaining 67 patients (29.6%) were thought to be occupationally handicapped at some level. In this group, 35 were partially disabled both before and after radiosurgery; however, in 15 instances a patient's working capacity increased from "not at all" to "partial." Seventeen patients were listed as totally disabled both prior to and following treatment. Eight patients who had a normal working capacity before treatment described themselves as occupationally handicapped at the time of the follow-up contact. This deterioration was a result of AVM rebleeding in three cases and radiation-induced damage in two other instances. Severe depression was the cause of disability in one patient, while another case involved a young man who suffers from chronic epilepsy. Employment. A total of 158 patients (69.3%) were either employed or functioning at a satisfactory level as students or housewives (11 cases) both prior to and after radiosurgery (Table 2). Another 42 patients were unable to work either before or after their treatment; however, five of these are retired and one is a man with chronic renal failure who has been receiving permanent disability payments. In 16 instances, patients who were previously unemployed are now working. Meanwhile, 12 patients who were working at the time of radiosurgery are currently not doing so. In this last group is a man whose working capacity deteriorated because of a rebleed. Additionally, there are four older patients who retired after their treatment and a young man who sustained an arm injury and is now unemployable. The circumstances surrounding the loss of employment in the remaining cases are not known. Sexual Function. The answers to an inquiry into sexual function are heavily influenced both by each patient's system of values and his or her age. Despite these limitations, the answers to this question can reflect some measure of general well-being. Given these provisos, 185 patients (81.1%) reported having normal agerelated sexual function both prior to and after radiosurgery (Table 2). This group includes children who largely because of their age, may not have been sexually active. Sexual activity was reduced or absent before treatment J. Neurosurg. / Volume 77~July, 1992
TABLE 2 Functional recoveryfollowing radiosurgery in 228 patients Cases
Functional Recovery Level occupational capacity full capacity same as before surgery improved following surgery occupationally handicapped partial before & after improved from no capacity total before & after actual employment employed before & after employed after not employed after unable before & after sexual function normal before & after improved after reduced after reduced or absent before & after
No.
Percent
162 127 35 67 35 15 17
71.1 78.4 21.6 29.6 53.0 22.7 24.3
158 16 12 42
69.3 7.0 5.3 18.4
185 21 9 13
81.1 9.2 3.9 5.7
and at the time of follow-up review in another 13 patients. In 21 cases there was an improvement in sexual function between the time of radiosurgery and follow-up data acquisition, while nine patients reported a decline in sexual function. This response was not related to any new neurological deficits and was prompted more commonly by the death of a spouse or by age-dependent psychological changes (Table 2). Mortality. As of May 1, 1986, 11 of the 239 patients for whom follow-up information was available had died. Recurrent hemorrhage was the cause of death in five patients and one patient committed suicide because of intractable pain syndrome originating with his initial AVM rupture. The causes of death in the remaining five patients were unrelated to the AVM or to radiosurgery. Discussion Radiosurgery is an effective method for the treatment of AVM. The gamma knife radiosurgical procedure for AVM has been described previously. 18"31'33"34"38"39 The results obtained were good in terms of both total obliteration of AVM and an overall functional outcome, and are comparable with the best published results of microsurgery, especially those series involving poorly accessible AVM's. 5-7"12-14'22'23'25'28-30'41-43
Referral Bias Relative to other series of AVM's our study includes an unusually high incidence of ruptured lesions (94%) and a corresponding small number of seizures as initial symptoms. This predominance of hemorrhagic presentation most likely reflects a referral bias. Angiographic Outcome Angiographic results of radiosurgical treatment of 5
L. Steiner, et al. AVM's have been extensively reported by Steiner, et al. 20'36'38-40 At the different follow-up stages of our material between 1977 and 1991, the cumulative incidence of total obliteration of AVM's varied between 79% and 95%. 20`35-40 Neurological Outcome The present report focuses on posttreatment neurological outcome and rebleeding. Many patients have experienced total or nearly total resolution of preexisting neurological deficits after radiosurgery. Improvement in the neurological condition of patients treated by radiosurgery may occur in the natural course of the disease, so caution is called for when evaluating amelioration of neurological deficits. Although most gains in neurological function seem attributable to the post-hemorrhage recovery process, it is still plausible that vascular steal was responsible for a few patients' symptoms. In such cases, neurological deficits could potentially improve if radiosurgical treatment would lead to either total or near total obliteration of the AVM. Headache. The disappearance of headache could often be correlated with AVM obliteration. This association was not absolute, however, and in several patients headaches persisted after complete AVM obliteration. Seizures. Seizure was the presenting symptom in 59 of the 247 patients in this series. Radiosurgery resulted in cessation of seizures, with or without anticonvulsant drugs, in 41 of these patients. Resolution of the seizure disorders was confounded by the fact that anticonvulsant medications were started or drug levels optimized in several cases at the time of or shortly after radiosurgery. Nevertheless, 11 patients who had chronic epilepsy and took medication prior to radiosurgery became seizure-free and could stop their anticonvulsant drugs. In three of these cases, this apparent "cure" of epilepsy occurred without obliteration of the AVM. From this observation one may speculate that the radiosurgical treatment had a direct effect on the epileptic neurons, ameliorating the seizure condition. Observations of Elomaa, 8'9 Barcia-Salorio, et al., L2 and Rossi, et aL, 27 support these assumptions. Further studies continue to clarify this hypothesis. There were 11 patients with new seizures. Concerning these cases, it should be remembered that all had suffered intracerebral hemorrhages before treatment, with extensive brain tissue damage in some. Protection Against Rebleeding Following Radiosurgery The contention that protection against rebleeding can be conferred without AVM obliteration ~6'~7is at odds with the consensus among neurosurgeons (shared by the authors) that patients remain at risk for rebleeding as long as the malformation is still patent, whether treated by microsurgery, radiosurgery, or endovascular techniques. The rebleed rates in irradiated but nonob6
literated AVM's suggest that radiation itself is not protective against subsequent rupture. This is particularly apparent with the person-year assessment method, which calculates the risk on the total follow-up period. The actual rebleed rate must lie somewhere between 1.9% and 6.5% which is not very dissimilar to the typical values reported for untreated AVM's of between 2% and 3%~yr. 3,4,t~ However, the answer is less clearcut with the Kaplan-Meier life-table method, which calculates the risk based on the time of followup study prior to the hemorrhagic events. According to the life-table estimates, radiosurgery does not appear to confer any significant protection against rebleeding in the nonobliterated AVM in the first 5 years following treatment. However, after this period the life table ends in a plateau which could be interpreted as an indication of a sustained decrease in the risk of hemorrhage late in the follow-up period (Fig. 2). There are serious arguments against such a conclusion. Peto, et al., 26 contend that any conclusion based on the fine detail of such a graph (life table) is likely to be wrong. According to them, particularly long fiat regions at the right end of the life table do not imply that the real risk of death (or other events such as bleeding) among patients who are still alive is negligible, unless a large number of patients have observation times well into or beyond the fiat regions. Our analysis of hemorrhage with a life table falls short of being conclusive because of the relatively small number of patients at risk for bleeds in the late follow-up period. It is important to note that the premise of Peto, et al., is referenced to an example comprising 102 patients. In focusing on finer details of the life table for hemorrhage in our patients with nonobliterated AVM's, the imprecision of estimates in the late follow-up period precludes strong conclusions regarding the plateau. The true risk of hemorrhage at 60 months is likely (p = 0.95) to be between 4% and 18% (rounded to the nearest integer). Moreover, the upper bound of the 95 % confidence interval for hemorrhage at the end of the observation period is not higher than 18%. In fact, it is probably lower than 18% due to losses from the followup group. This 18% to 20% rate at 96 months is a possible, albeit improbable, value for hemorrhage at the end of the observation period and is consistent with a risk that is constant over the entire follow-up period. Although according to Peto, et al., 26 the plateau at the right end of the life curve is not pertinent, it is difficult to ignore in practice. Actually, based on a Poisson model of risk, a rate for hemorrhage as high as 1.2%/yr would yield confidence limits including 0. To be sure, a lower rate might be explained by the fact that the majority of the AVM's under scrutiny may have been obliterated and thus the number of individuals at risk for bleeding was lower. Indeed, it cannot be totally excluded that additional cure might have occurred and was not discovered between the time of the last anglogram and completion of the follow-up period (December 31, 1988). Furthermore, the possibility of inadeJ. Neurosurg. / Volume 77~July, 1992
Outcome of radiosurgery for arteriovenous malformations quate assessment by the referring physician or failure of the patient to see a physician if the symptoms were discrete should not be dismissed. In spite of strong evidence to the contrary, the contention that radiosurgery does confer protection against rebleeding in a still-patent AVM may have major influence on the thinking of physicians involved in the management of these patients. Therefore, the pertinence of information provided by the life-curve method should be studied carefully in a large series of patients with long follow-up intervals.
Conclusions Radiosurgery induces a high incidence o f angiographically proven obliteration of A V M ' s with a relatively low incidence of undue side effects. Although there is a suggestion of improvement in pretreatment symptoms, any relation with the treatment still remains to be proved. We believe that protection against rebleeding occurs only if the AVM is totally obliterated. Nevertheless, since the life-curve method suggests incongruities in this respect, the problem should be further investigated in large series of patients observed over a long period of time.
Acknowledgments We wish to express our warm thanks to Drs. John G. Ferguson and Ralph F. Frankowski for their valuable suggestions in interpreting the life-table findings. We thank also Mrs. Lucille Staiger, Mrs. Ruth Clawson, and Mrs. Terri Moulton who assisted in the preparation of the manuscript and illustrations.
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Manuscript received February 15, 1991. Accepted in final form December 17, 1991. Address for Dr. Adler: Department of Neurosurgery, Stanford Medical Center, Stanford, California. Address for Dr. Torner: Department of Preventive Medicine and Environmental Health, University of Iowa, Iowa City, Iowa. Address reprint requests to: Ladislau Steiner, M.D., Ph.D., Department of Neurological Surgery, University of Virginia, Health Sciences Center, Box 212, Charlottesville, Virginia 22908.
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