(Stroke. 1996;27:1-6.)
© 1996 American Heart Association, Inc.
Articles |
From the Departments of Neurological Surgery (B.E.P., J.C.F., L.D.L., D.J.B., D.K.), Radiation Oncology (J.C.F., L.D.L., D.K.), and Radiology (L.D.L.), University of Pittsburgh (Pa) Medical Center.
Correspondence to Bruce E. Pollock, MD, and reprint requests to L. Dade Lunsford, MD, FACS, Department of Neurological Surgery, Presbyterian University Hospital, 200 Lothrop St, Pittsburgh, PA 15213.
| Abstract |
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Methods We reviewed the clinical histories and cerebral angiograms of 315 AVM patients who underwent stereotactic radiosurgery at our center. One half of the patient data (analysis cohort) was used to determine risk factors for bleeding and to construct AVM hemorrhage risk groups. These risk groups were then tested with the second half of the patient data (test cohort).
Results The mean AVM volume was 4.0±3.4 mL (approximate maximum diameter of 2 cm). One hundred ninety-six initial hemorrhages occurred in 10 348 patient-years for an annual initial bleed rate of 1.89%; 44 of these 196 patients had a repeat bleed in 591 patient-years for an annual rebleed rate of 7.45%. The overall crude annual hemorrhage rate was 2.40%. Multivariate analysis revealed three factors associated with hemorrhage: history of a prior bleed (relative risk [RR], 9.09; 95% confidence interval [CI], 5.44 to 15.19; P<.001), a single draining vein (RR, 1.66; 95% CI, 1.13 to 2.38; P<.01), and a diffuse AVM morphology (RR, 1.64; 95% CI, 1.12 to 2.46; P<.01). Four AVM hemorrhage risk groups were constructed on the basis of the significant factors. The annual rate of bleeding was 0.99% for low-risk AVMs, 2.22% for intermediate-lowrisk AVMs, 3.72% for intermediate-highrisk AVMs, and 8.94% for high-risk AVMs.
Conclusions Analysis of a large group of AVM patients who underwent stereotactic radiosurgery demonstrated that small AVMs have an annual hemorrhage risk similar to that of the general AVM population. AVM patients have a wide variability of bleeding risk that can be predicted from their clinical presentation and the angiographic characteristics of the AVM. The management of AVM patients should be based not only on the morbidity of the proposed treatment but also those factors that predispose individual patients to either a low or high hemorrhage risk.
Key Words: cerebral arteriovenous malformation hemorrhage natural history
| Introduction |
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Newly diagnosed AVM patients usually are advised to undergo surgical resection of the malformation if the anticipated morbidity of the operation is low.17 18 19 This management approach assumes that the risk of bleeding over a patient's lifetime is substantial and that all AVMs have a similar risk of hemorrhage. To better understand the risk factors associated with AVM hemorrhage, we retrospectively reviewed the clinical histories and radiographic studies of 315 AVM patients who underwent stereotactic radiosurgery at our center before 1992. Because the purpose of this report was to examine the natural history of untreated AVMs, the bleeding rate of these AVM patients after radiosurgery was not included in the present study.
| Subjects and Methods |
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Study Design
We reviewed the outpatient and hospital records
of all
patients to determine their clinical histories. We contacted the
referring physician or the patient when further information was needed.
To determine the annual hemorrhage rate for the study
population before stereotactic radiosurgery, we
recorded the time from each patient's birth date to all documented
AVM hemorrhages (confirmed by either CT, lumbar puncture, or
operative report) and to the date of radiosurgery. The time patients
were at risk for an initial AVM hemorrhage was defined as the
time from each patient's date of birth to either a documented bleed or
until the date of radiosurgery. The time patients were at risk for
rebleeding was defined as the time from a patient's initial AVM
hemorrhage to either a rebleed or to the date of radiosurgery.
To calculate the annual initial hemorrhage rate, the number of
initial AVM hemorrhages observed was divided by the total
number of patient-years that the study population was at risk for
an initial hemorrhage. To calculate the annual rebleed rate,
the number of repeat AVM hemorrhages observed was divided by
the total number of patient-years that the study population was at
risk for rebleeding.
The stereotactic angiograms and MRI studies of
every
patient were reviewed, and the following information for each AVM was
recorded: location, hemispheric (cerebral or cerebellar lobes)
versus deep (thalamus, basal ganglia, corpus callosum, or brain stem);
volume (V=
/6 ·X · Y · Z dimensions);
morphology (compact
versus diffuse) (Fig 1
); proximity to a pial or
ependymal surface (yes versus no); venous drainage (superficial versus
deep versus both); number of draining veins (1 versus >1) (Fig
2
); related aneurysms (proximal or intranidal
versus none or unrelated); and presence of a varix (yes versus no).
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Statistical Analysis
The patient population was randomly
divided into two groups (A
and B). Hemorrhage risk data for both groups were separated
into initial hemorrhage risk data (AI and
BI) and rebleed risk data (AR and
BR). To prevent any bias that may have occurred in the
grouping of the patients, a crossover of patients was incorporated at
the time of initial AVM hemorrhage. The data set
(analysis cohort) for the univariate and
multivariate analyses of AVM hemorrhage
risk factors consisted of the initial hemorrhage risk data from
group A patients combined with the rebleed risk data from group B
patients (AI+BR). AVM risk groups were then
constructed on the basis of the results from the
analysis-cohort data evaluation. The validity of the AVM
risk groups was then verified on the remaining data set (test cohort)
consisting of the initial hemorrhage risk data from group B
patients combined with the rebleed risk data from group A patients
(BI+AR).
Actuarial risks of hemorrhage were calculated with the Kaplan-Meier method.20 Observations on all patients were censored at the time of their radiosurgical procedure. Univariate analysis of clinical and radiographic AVM factors was performed with the log-rank test,21 and a stepwise multivariate analysis was performed with the Cox proportional hazards model to identify independent risk factors.22 Patient age was tested as a time-dependent covariate by the proportional hazards model for both the univariate and multivariate analyses.
| Results |
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Risk Factors for AVM Hemorrhage
Initial univariate analysis
of clinical and
radiographic AVM factors revealed six significant risk
factors for hemorrhage: history of a prior bleed
(P<.001), deep location (P<.001), deep venous
drainage (P<.001), increasing patient age
(P<.001), diffuse AVM morphology (P<.001), and
one draining vein (P=.046). Eighty-four of 97 patients
(87%) with deeply located AVMs presented after a
hemorrhage compared with 112 of 218 patients (51%) with
hemispheric AVMs (P<.001). This was felt to
represent a presentation bias rather than a true
risk factor for AVM hemorrhage and was removed from further
analyses. Deep venous drainage was also excluded from further
analyses because it strongly correlated with AVM location; 92
of 97 patients (95%) with deeply located AVMs had some component of
deep venous drainage compared with 131 of 218 patients (60%)
with hemispheric AVMs (P<.001). Exclusion of location and
deep venous drainage because of presentation bias was
supported by subset univariate analysis of
subsequent hemorrhage risk in which neither factor was
significant (location, P=.40; deep venous drainage,
P=.37).
The results of the univariate analysis for
the remaining factors are shown in Table 2
.
Multivariate analysis revealed three
significant risk factors associated with hemorrhage: history of
a prior bleed (relative risk [RR], 9.09; 95% confidence interval
[CI], 5.44 to 15.19; P<.001), a single draining vein
(RR,
1.66; 95% CI, 1.13 to 2.38; P<.01), and diffuse AVM
morphology (RR, 1.64; CI, 1.12 to 2.46; P<.01).
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Development and Testing of AVM Risk Groups
Four AVM risk
groups were constructed on the basis of the three
significant variables of the multivariate
analysis. Low-risk AVMs had no history of a prior bleed,
>1 draining vein, and a compact nidus. Intermediate-lowrisk
AVMs had no history of a prior bleed, 1 draining vein, and/or a diffuse
nidus. Intermediate-highrisk AVMs had a history of a prior
bleed, >1 draining vein, and a compact nidus. High-risk AVMs had a
history of a prior bleed, 1 draining vein, and/or a diffuse nidus. The
AVM risk groups were then included in a separate
multivariate analysis with the previously
tested factors. In that analysis the AVM risk group assigned to
each AVM was the only variable predictive of hemorrhage
(RR, 2.34; 95% CI, 1.79 to 3.06; P<.001).
The annual rates
of hemorrhage when the AVM risk groups were
applied to the test cohort were 1.31% for low-risk AVMs, 2.40%
for both intermediate-risk AVM groups, and 8.99% for high-risk
AVMs. Table 3
shows the annual rates of
hemorrhage when the AVM risk groups were applied to the entire
study population. Inclusion of the entire study population to determine
the annual hemorrhage rates for the AVM risk groups was
necessary due to the small number of intermediate-highrisk
patients in the test cohort (n=13). The RR for each step of the model
was 1.60 (95% CI, 1.36 to 1.87; P<.001). Fig 3
shows the actuarial hemorrhage rates for the
AVM risk groups when applied to the entire study population.
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| Discussion |
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Published reports on AVMs may be divided into two types: natural-history studies4 5 6 7 8 9 10 and descriptive studies.11 12 13 14 15 Natural-history studies follow a group of AVM patients over time to determine bleeding rates and patient outcomes. Descriptive studies generally are based on a surgical series and examine clinical, anatomic, and physiological factors predictive of bleeding. There are weaknesses associated with both study types. First, both types of studies are hampered by selection bias. Patients with large or critically located AVMs are poor candidates for surgical removal, and observation is generally recommended. Patients with small AVMs in surgically accessible brain regions are candidates for surgical resection, since little morbidity is associated with removal of these AVMs. Second, most natural-history studies enrolled patients before the modern era of neuroimaging.5 6 7 8 9 10 These studies provide little information on the angioarchitecture of the malformations. Third, the results of descriptive studies are often confounded because factors associated with a clinical presentation of hemorrhage are mistaken for factors predictive of bleeding (ie, small AVM size, deep location). Fourth, descriptive studies (including the present series) can only calculate the nonfatal hemorrhage rate, since patients with initially fatal AVM hemorrhages never receive treatment. In such studies, the overall hemorrhage rate would be underestimated by 10% to 29% (the reported mortality rate for each AVM hemorrhage).3 4 7 8 10 To date, no study has enabled physicians to accurately predict the bleeding risk for individual AVM patients on the basis of clinical presentation and the radiological characteristics of the malformation.
Three assumptions were made in the data analysis that may limit the findings of the present study. First, a potential selection bias was present because the study population consisted only of patients who underwent stereotactic radiosurgery. Such patients generally have AVMs <3 cm in average diameter (87% in the present series), and these AVMs are often located in critical brain locations (31% were "deep" AVMs in the present series). Published natural-history studies have contained from 17% to 30% small AVMs and from 9% to 32% "deep" AVMs.4 5 7 8 9 Therefore, caution should be used when applying the current results to the general AVM population. Second, it was assumed that all AVMs are congenital. This is a reasonable assumption based on large surgical and autopsy series.2 25 Third, it was assumed that an AVM has the same risk of hemorrhage throughout a patient's life. Although the natural history of pediatric AVMs is poorly understood, it is recognized that the majority of pediatric AVMs are discovered after a hemorrhage.3 7 30 31 It remains unclear whether the changes in AVM morphology that occur throughout childhood and adolescence affect the risk of hemorrhage. This important question has not been settled; therefore, our findings may be more appropriate for the adult AVM population.
The present study found that a history of prior hemorrhage was the factor most predictive of future bleeding. The annual initial hemorrhage rate was 1.89% compared with the annual rebleeding rate of 7.45%. Previously published AVM natural-history studies have reported an overall 2% to 4% annual hemorrhage rate.4 5 6 7 8 9 10 The rebleeding rate for the year after hemorrhage has been reported to vary between 6% and 18%.6 7 8 9 It then returns to an approximately 2% to 3% rate of bleeding in subsequent years. Brown et al4 reported 168 patients with unruptured AVMs and observed 14 patients with nonfatal AVM bleeds who did not undergo further treatment; no patient sustained a repeat bleed. The authors state that the lack of recurrent hemorrhage was likely due to the short follow-up of these patients (mean follow-up, 58 months). Ondra et al10 reported a population-based prospective study of all symptomatic AVM patients in Finland from 1942 to 1975. They found an annual hemorrhage rate of 4.0%, regardless of the clinical presentation of the patient. Despite the completeness and length of follow-up in this study (mean follow-up, 23.7 years), the frequency of new hemorrhagic events was analyzed in 5-year intervals. It is possible that a transient increase in the bleeding rate of patients with a previous hemorrhage was not detected by their statistical analysis.
Patients with small AVMs more commonly present with hemorrhage. Whether the risk of bleeding is affected by the size of the malformation remains a controversial issue.11 12 Small AVMs (<3 cm in diameter) may have the same annual hemorrhage rate as larger AVMs but may be less likely to cause seizures or headaches that might lead to their clinical detection. Graf et al8 found small AVM size to be a risk factor for initial AVM hemorrhage. However, only 12 of 71 patients with unruptured AVMs <3 cm in diameter were included in their study. Of 134 patients with a history of hemorrhage, 51 had AVMs <3 cm in diameter, and AVM size was not found to increase the risk of rebleeding. Most natural-history AVM studies have reported that small AVMs more commonly present with hemorrhage, but these studies have found no correlation between AVM size and subsequent bleeds.5 6 7 9 Brown et al4 did not find AVM size to be related to bleeding risk in a series of unruptured AVMs. Because the majority of AVMs in the present series were <3 cm in diameter (the upper size limit for optimal AVM radiosurgery), the expected annual hemorrhage rate in our series should be greater than the commonly quoted 2% to 4% rate for AVMs of all sizes if small AVMs have a higher annual hemorrhage rate.4 5 6 7 8 9 10 The overall hemorrhage rate in our series was 2.40%. Therefore, our results are supported by published AVM natural-history studies: small AVM size does not increase the risk of AVM bleeding.
A number of anatomic AVM characteristics have been reported to predispose AVM patients to bleeding. The present study found diffuse AVM morphology and a single draining vein to be independent angiographic predictors of hemorrhage. Miyasaka et al14 analyzed the venous drainage system as a factor in AVM hemorrhage and found three variables associated with hemorrhage: a single draining vein, impaired venous drainage, and deep venous drainage alone. Unfortunately, no multivariate analysis of these factors was performed, and the location of the AVMs in relation to their venous drainage was not specified. Kader et al11 also found deep venous drainage to be an independent risk factor for AVM bleeding, but this characteristic may be confounded by its relation to AVM location (as in the present series). Deeply located AVMs are unlikely to cause seizures, and patients are usually diagnosed after an intracerebral hemorrhage.
Recent reports have studied the intravascular pressures of AVMs and found that feeding artery pressures were greater in ruptured versus unruptured AVMs.11 12 Spetzler et al12 found an inverse relationship between feeding artery pressure size and AVM size, whereas Kader et al11 reported that feeding artery pressure was only weakly related to the size of the lesion. It remains unclear whether the increase in feeding artery pressure is an important factor in the pathophysiology of AVM hemorrhage or the hemodynamic sequelae of the AVM rupture. Young et al32 examined AVM venous physiology and discovered that there was a direct relationship between feeding artery and draining vein pressures. Draining vein pressure was affected more by changes in the patient's central venous pressure than elevations in the mean arterial pressure. Draining vein pressure was neither predictive of AVM hemorrhage nor related to AVM size, AVM location, or the direction of the venous drainage. These results are contrary to the hypothesis that restriction of venous outflow from an AVM is the primary determinant of AVM rupture.33 Clearly, more information is needed to determine which hemodynamic aberrations result in AVM hemorrhage.
The coexistence of AVMs and cerebral aneurysms has been documented in 6% to 19% of AVM patients.3 4 5 7 13 16 34 35 Aneurysms related to the AVM may occur on arteries proximal to the malformation or within the substance of the nidus. The pathogenesis of related aneurysms is believed to be either a consequence of the high flow through the AVM or due to a shared developmental abnormality that weakens the cerebral vasculature. Marks et al13 reviewed the cerebral angiograms of 65 patients and found that all patients with intranidal aneurysms (n=9) presented with hemorrhage. Turjman et al15 reported that 58 of 100 AVM patients studied with superselective angiography had related aneurysms. Presence of a related aneurysm and intranidal aneurysm location were found to correlate with a clinical presentation of hemorrhage. The percentage of related aneurysms (58%) reported in that series is much higher than previously reported and probably relates to the use of superselective angiography to study the AVMs.
We found related aneurysms in 24 of 315 AVM patients (8%), but their presence was not predictive of bleeding (P=.63). The discrepancy between our findings and prior reports has several possible explanations. First, we may not have detected the true number of intranidal aneurysms in our AVM patients, since our results were based on the stereotactic angiograms performed at the time of radiosurgery. This technique is unlikely to be as sensitive as superselective angiography in detailing the angioarchitecture of cerebral AVMs.15 Second, intranidal aneurysms may be pseudoaneurysms that form at the site of an AVM rupture and are repaired after the bleeding episode. Thus, their detection may relate to the timing of angiography in relation to the bleeding episode. Patients in our series were studied angiographically at a median of 6 months (mean, 16 months) after their last hemorrhage. Nonetheless, we remain concerned that the presence of an intranidal aneurysm may be a significant risk factor for AVM hemorrhage, and further investigation is warranted.
The results of this study show that AVM patients are a heterogeneous population with respect to their risk of hemorrhage. Such heterogeneity has significant clinical ramifications. AVMs discovered incidentally in elderly patients may be managed conservatively because the patient's lifetime hemorrhage risk is low. Patients with low-hemorrhage-risk AVMs should be considered ideal candidates for stereotactic radiosurgery because their risk of hemorrhage during the latency interval before AVM obliteration is less than 3%. Conversely, patients with high-hemorrhage-risk AVMs have a greater than 25% chance of bleeding during the latency interval after stereotactic radiosurgery and should undergo removal of their AVM if it is in an accessible brain location. Thus, the management of AVM patients should be based on both the bleeding risk for each individual malformation and the morbidity of the proposed treatment.
Received August 1, 1995; revision received September 29, 1995; accepted September 29, 1995.
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