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A
rteriovenous malformations (AVM) of The complex cerebrovascular anatomy of
Reprint requests:
Aki Laakso, M.D., Ph.D., the brain are congenital vascular lesions AVMs makes them a challenge to treat, and the
Department of Neurosurgery, that account for approximately 2% of all treatment itself carries significant risks. To eval-
Helsinki University hemorrhagic strokes (2, 5). Despite the relative uate the possible benefit of a risky treatment,
Central Hospital, rarity of the disease (with an estimated current one needs to understand the natural history
Topeliuksenkatu 5,
P.O. Box 266,
detection rate of approximately 1/100 000 and prognosis of the disease. The complexity of
Helsinki, FIN-00029-HUS, Finland. person-years) (2), AVMs pose a significant neu- AVMs makes them a rather heterogeneous
Email: aki.laakso@hus.fi rological problem because patients are mostly group of lesions in terms of various factors pos-
young and otherwise healthy. Moreover, the sibly affecting the risk of rupture and subse-
Received, February 6, 2008. availability of noninvasive imaging has rapidly quent hemorrhagic stroke. Over the past sev-
Accepted, June 26, 2008. increased the detection of incidental AVMs. eral decades, several groups have contributed
to our knowledge of the hemorrhage risk asso-
ciated with untreated AVMs (1, 3, 4, 6–9, 11,
ABBREVIATION: AVM, arteriovenous malforma-
13–15, 17, 19, 20, 22). The existing literature,
tion.
however, is inconclusive about both the annual
rupture rate and the factors affecting this risk. Some of the patients were followed until death, the first new occurrence of hemor-
inconsistencies between older and recent reports are explained rhagic stroke, initiation of any treatment of the AVM (neurosurgical,
by the use of more sophisticated statistical methods in the lat- endovascular, or radiosurgical), or last contact (at the end of 2005). Only
ter. At the same time, however, the development of therapeu- patients with at least 1 month of hemorrhage- and treatment-free sur-
tic strategies has made it increasingly rare that a large propor- vival time were included for further analysis. The characteristics of
patients experiencing an AVM rupture during the follow-up period
tion of patients would be followed conservatively; therefore,
were compared with rupture-free patients using Pearson’s χ2 test for cat-
historical patient cohorts have significant inherent value egorical variables and the Mann-Whitney U test for age and follow-up
because of the lack of selection bias. time. The annual risk of AVM rupture was calculated as the number of
Finland is well suited for population-based epidemiological patients with new hemorrhage during follow-up divided by person-
studies because of a high-quality public health care system in years of follow-up. Cumulative rates of AVM rupture were estimated
which AVMs are treated in public university hospitals with using the Kaplan-Meier product-limit method, and the resulting curves
population-wide responsibility, comprehensive and accessible were compared using the log-rank test. The Cox proportional hazards
hospital records and vital statistics, and a relatively stable and model with a forward stepwise regression procedure was used to deter-
homogeneous population. One of the most cited studies on the mine the significance of several variables in predicting the relative risk
natural history of patients with AVMs is based on a series of (hazard ratio) of subsequent AVM rupture. These variables were age;
sex; AVM rupture before admission; AVM size (categorized as small
160 patients admitted to the Department of Neurosurgery at
[⬍2.5 cm in diameter], medium [2.5–5.0 cm], or large [⬎5 cm]); infra- or
Helsinki University Central Hospital between 1942 and 1975 supratentorial location and deep or superficial location; pattern of
(15). We have now extended that series to include 238 patients venous drainage (categorized as superficial, deep, or both superficial
admitted between 1942 and 2005 and applied Kaplan-Meier and deep); and interactions between rupture status, size, location, and
life table analyses and Cox proportional hazards regression venous drainage pattern. Because of the observation that annual rupture
models to define the annual risk of hemorrhage and risk factors rates were highest during the first few years after diagnosis, log-rank
for hemorrhage. tests and Cox regression analyses were performed not only for the
whole follow-up period but also for only the first 5 years. A 2-tailed
P value of less than 0.05 was considered statistically significant.
PATIENTS AND METHODS
Patients RESULTS
All 631 consecutive patients with AVMs who were admitted to the All Patients
Department of Neurosurgery at Helsinki University Central Hospital
(current catchment population of almost 2 million people) from 1942 to Of the 631 AVM patients admitted between 1942 and 2005, 393
2005 were identified. This department was the only neurosurgical clinic patients had less than 1 month of hemorrhage- and treatment-
in Finland until the late 1960s. A diagnosis of AVM was based on angiog- free follow-up time: 7 had died, 1 had recurrent bleeding, 2 were
raphy or histology. Patients with spinal AVMs, dural arteriovenous fis- discharged abroad, and treatment was initiated in 383 patients
tulae, caroticocavernous fistulae, and vein of Galen aneurysms were not within the first month after admission. Thus, 238 AVM patients
included in the study. Size, location, and angioarchitecture of AVMs were included in further analyses (see Table 1 for details). More
were evaluated from angiography, computed tomography, or magnetic than three-fourths (182 patients, 77%) of patients had been
resonance imaging studies. Because a detailed characterization of various admitted before the end of 1980s. During the same period, how-
types of associated aneurysms (incidental, flow related, intranidal, or ever, only 54% (199 of 368) of all patients admitted before the end
venous) was not readily available for all older cases, we decided not to
of 1980s had received any treatment for their AVM, demonstrat-
include the existence of aneurysms in the statistical analysis. Anterior
and posterior paracallosal, basal ganglia, intraventricular, trigonal, tem-
ing the rather conservative treatment policy of the period from
poromesial, pontomesencephalic, and deep cerebellar AVMs were con- which most of the follow-up data have been gathered. The mean
sidered deep and all other locations superficial. Pontomesencephalic and follow-up period was 13.5 years (range, 1 month–53.1 years).
cerebellar AVMs were considered infratentorial and all other locations Complete follow-up was obtained for all but 3 (1.3%) patients.
supratentorial. An AVM was considered ruptured before admission if AVMs had ruptured in 139 patients before admission. The diag-
there were signs of bleeding on a computed tomographic scan or lumbar nosis of previous hemorrhage was based on history alone in 19
puncture or if a patient had a history of severe, sudden headache and patients and was verified by computed tomography, magnetic
bleeding was not ruled out. The severity of an AVM rupture was esti- resonance imaging, lumbar puncture, or operative findings in
mated from hospital records when possible and scored according to the the remainder of the patients. During the total follow-up period
classification of Hunt and Hess (10), in which increasing severity corre-
of 3222 person-years, 77 patients experienced a hemorrhage from
sponds to increasing grade (Grades 1–5). All available follow-up data
were collected starting from the admission to a neurosurgical referral
AVM, yielding an overall annual rupture rate of 2.4%. The sever-
center until death or the end of the year 2005. The study was approved ity of hemorrhage on the Hunt and Hess scale was Grade 1 in 2
by the ethical committee of Helsinki University Central Hospital. patients (3%), Grade 2 in 23 (30%), Grade 3 in 13 (17%), Grade 4
in 8 (10%), Grade 5 in 24 (31%), and could not been reliably esti-
Statistical Methods mated retrospectively in 7 (9%) patients. The risk of new hemor-
Statistical analysis was performed by two authors (AL, SJ) using SPSS rhagic event was highest during the first few years after diagno-
software (version 13.0; SPSS Inc., Chicago, IL). For the purpose of life sis. The annual rupture rate was almost 3 times higher during
table analyses and the Cox proportional hazards regression model, the first 5 years (4.6%) than thereafter (1.6%) (Fig. 1A; Table 2).
Univariate Analyses of Risk Factors for Rupture almost 12% during the first 5 years in infratentorial AVMs
The characteristics of patients who experienced an AVM rup- (Table 2). Similarly, cumulative rupture rates were very vari-
ture during the follow-up period are compared with those who able, ranging from 18% in 20 years in AVMs with both cortical
remained rupture-free in Table 1. Patients with an AVM rupture and deep venous drainage to 76% in 20 years in infratentorial
during the follow-up period were significantly younger at the AVMs (Table 2).
time of admission and were more likely to have a previously Univariate Cox regression analysis (Table 3) revealed that pre-
ruptured AVM and a deeply located AVM (Table 1). vious rupture, infratentorial location, and deep location were
Previous rupture, infratentorial location, and deep location associated with a significantly increased relative risk (approxi-
were associated with significantly higher AVM rupture rates mately 2- to 2.5-fold) for AVM rupture during the entire fol-
during the entire follow-up period than previously unruptured, low-up period. Exclusively deep venous drainage increased the
supratentorial, or superficially located AVMs, respectively (Fig. relative risk significantly more than sixfold for the first 5 years
1, B, D, and E; Table 2). Exclusively deep venous drainage but not for the entire follow-up period. Age, sex, and AVM size
increased the AVM rupture rate significantly only during the did not affect rupture risk in univariate analysis.
first 5 years, but not during the entire follow-up period (Fig. 1F;
Table 2). Sex and AVM size did not significantly affect the rup- Multivariate Analyses of Risk Factors for Rupture
ture rate (Fig. 1C; Table 2). Annual rupture rates varied sub- We performed multivariate Cox regression analyses to define
stantially, depending on stratifying factors and time point, from independent risk factors for AVM rupture using 3 different mod-
1.0% later than 5 years from admission in small AVMs to els (Table 3). First, we used a forward stepwise procedure to test all
DISCUSSION
Our natural history study
has the longest follow-up per
AVM patient ever published
and only modest selection
FIGURE 1. Kaplan-Meier curves demonstrating cumulative rates of arteriovenous malformation rupture as the func-
bias. Although patient selec-
tion of follow-up time in years: all patients together (A) and patients stratified by previous rupture (B), AVM size tion to active treatment may
(C), superficial or deep location (D), supra- or infratentorial location (E), and pattern of venous drainage (F). See introduce some bias influenc-
Table 2 for the number of patients in each stratum. BAVM, brain arteriovenous malformation; vs., versus. ing the results (i.e., the least
complex lesions are most
likely to be treated early, lead-
variables listed in Table 3, excluding interactions between vari- ing to shorter natural history follow-up time), there are 2 fac-
ables. According to this model, previous rupture and deep location tors in the current study that will perhaps decrease the impact
remained in the model as statistically significant independent risk of this bias. First, most of the follow-up time is from the period
factors for AVM rupture during the first 5 years and previous rup- before the 1990s when the treatment policy was rather conser-
TABLE 2. Annual and cumulative rupture rates in relation to previous rupture, supra- or infratentorial location, superficial or deep location,
arteriovenous malformation size, and pattern of venous drainagea
Cumulative rupture rates,
Annual rupture rates (%) Log-rank P values
% (95% CI)
No. of
Characteristic 0–5 years ⬎ 5 years Whole 5 years 20 years First 5 years Entire
patients
after after follow-up after after after follow-up
admission admission period admission admission admission period
All patients 238 4.7 1.6 2.4 21 (15–27) 39 (32–47)
Sex 0.265 0.250
Male 141 4.0 1.5 2.1 18 (11–25) 37 (27–47)
Female 97 5.8 1.7 2.8 25 (15–35) 43 (31–66)
Previous rupture 0.011 0.016
Ruptured 139 6.2 1.7 2.8 26 (19–34) 45 (27–63)
Unruptured 99 2.3 1.3 1.6 10 (3–17) 29 (16–42)
Supra- or infratentorial AVM 0.023 0.008
Supratentorial 218 4.3 1.5 2.2 19 (13–25) 37 (29–45)
Infratentorial 18 11.6 3.6 6.7 45 (18–72) 76 (51–100)
Superficial or deep AVM 0.003 0.003
Superficial 170 3.5 1.4 1.9 16 (10–22) 35 (27–44)
Deep 66 8.9 2.2 4.1 35 (22–49) 53 (38–67)
AVM size 0.807 0.220
Small 88 5.0 1.0 1.9 22 (12–32) 33 (21–45)
Medium 96 4.2 1.6 2.3 17 (9–26) 38 (25–51)
Large 47 5.5 2.7 3.5 24 (11–36) 52 (35–69)
Venous drainage 0.013 0.111
Cortical and deep 42 1.2 1.9 1.7 5 (0–13) 18 (3–33)
Cortical 122 4.5 1.4 2.1 20 (12–28) 38 (29–47)
Deep 64 8.1 1.6 3.4 34 (20–48) 52 (37–68)
a
AVM, arteriovenous malformation; CI, confidence interval.
vative compared with today’s standards, and, therefore, study by Ondra et al. (15) had a longer follow-up period, but
patients with a wide variety of lesions were followed untreated the authors did not stop the follow-up at the first bleeding
for a rather long period (often years). Second, even if the distri- event as should have been done for life table and annual rup-
bution of various demographic and anatomic factors in the ture rate analyses.
study cohort is influenced by the exclusion of certain patients We identified several risk factors predicting AVM rupture,
because of treatment, multivariate models were used to dissect including young age, previous rupture, large size, deep and
the independent effects of these factors. Its results indicate that infratentorial location, and exclusively deep venous drainage. The
previously ruptured, large, and infratentorially and deeply most consistent risk factor was previous rupture because it pre-
located AVMs have the highest risk of subsequent hemorrhage. dicted future rupture in practically all models. The highest rupture
This risk is highest during the first few years after diagnosis rate, almost 12% per year, was observed in infratentorial AVMs
and decreases thereafter. during the first 5 years after diagnosis, whereas the highest rela-
Management of patients with AVMs requires reliable knowl- tive risk, more than sixfold, was associated with AVMs with exclu-
edge of the natural course of the disease. Only with sufficient sively deep venous drainage during the same period. According
understanding of these complex lesions can treatment-associ- to multivariate analyses, previous rupture, large size, and infraten-
ated risks be weighed against the prognosis, leading to deci- torial and deep locations were independent risk factors. Moreover,
sions that will be beneficial for the patient. With a total follow- interaction between deep location and previous rupture was an
up time of 3222 person-years (mean, 13.5 person-years per independent risk factor, with a more than fourfold relative risk.
patient), our study is the most extensive natural history series The comparison of our results with those published by
of AVM patients analyzed using Kaplan-Meier life table analy- Ondra et al. (15) is inevitable because their patients are also
sis and Cox multivariate modeling published to date. The included in our series. Two important differences are readily
4.21 (1.19–14.9)b
1.65 (0.90–3.05)
Model 3 did not observe a significant difference in rup-
ture rate between patients with previously rup-
1.00
—
—
—
tured and unruptured AVMs as we did. The first
discrepancy is easily explained by different sta-
tistical methods. Instead of using Kaplan-Meier
Relative risk during the whole period (95% CI)
2.10 (0.90–4.91)
1.74 (0.93–3.27)
2.04 (0.82–5.13)
1.67 (0.67–4.15)
only until the first bleeding, they simply divided
Not tested
Model 2
1.00
1.00
many as 12 in one patient) by the total observa-
tion time. The second discrepancy is much more
difficult to explain, but is also likely related to
methodological differences. In our series, previ-
ous rupture predicted bleeding consistently and
b
3.13 (1.55–6.30)d
1.92 (1.12–3.29)b 2.23 (1.23–4.05)c
1.80 (0.98–3.32)
Not tested
Model 1
—
—
—
—
—
1.99 (1.24–3.17)
1.14 (0.66–1.97)
1.65 (0.92–2.94)
1.38 (0.67–2.87)
2.08 (0.97–4.49)
Univariate
Not tested
1.00
d
c
2.68 (0.98–7.32)
2.57 (0.76–0.86)
1.40 (0.60–3.27)
4.92 (0.98–24.7)
3.83 (0.78–18.8)
CI, confidence interval; Model 1, Cox proportional hazards model with a forward stepwise regression
procedure; Model 2, adjusted model with main effects; Model 3, Model 1 including interactions;
1.00
Relative risk during the first 5 years (95% CI)
b
2.04 (1.04–3.99)
—
—
—
—
—
—
2.65 (1.11–6.32)b
6.42 (1.48–27.9)b
c
0.98 (0.96–1.01)
0.70 (0.37–1.31)
2.50 (1.32–4.71)
0.85 (0.40–1.78)
1.10 (0.50–2.46)
3.59 (0.84–15.4)
Not tested
1.00
previous rupture
Characteristic
Deep location*
Infratentorial
Cortical
AVM size
Male sex
Location
Small
Large
Deep
Deep
Disclosures Acknowledgment
This work was supported by the Maire Taponen Foundation, the We thank Annika Kytölä, R.N., for assistance in gathering follow-up data
Paavo Nurmi Foundation, and the Neurological Foundation of Finland. from the patients.