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Risk of spontaneous haemorrhage after diagnosis of cerebral arteriovenous malformation
THE LANCET
Risk of spontaneous haemorrhage after diagnosis of cerebral arteriovenous malformation
Henning Mast, William L Young, Hans-Christian Koennecke, Robert R Sciacca, Andrei Osipov, John Pile-Spellman, Lotfi Hacein-Bey, Hoang Duong, Bennett M Stein, J P Mohr
Summary Background A small proportion of strokes are caused by cerebral arteriovenous malformations (AVM). Treatment to prevent intracranial haemorrhage itself carries risks, and untreated AVM may in many cases have a good prognosis. We investigated the risk of subsequent symptomatic bleeding in the clinical course of AVM in patients with and without an initial haemorrhage. Methods 281 unselected, consecutive, prospectively enrolled patients with cerebral AVM were grouped according to their initial clinical presentation—142 presented with and 139 without haemorrhage. The frequency of AVM haemorrhages during the subsequent clinical course (before the start of endovascular, surgical, or radiation treatment) in the two groups was compared by means of Kaplan-Meier life-tables, log-rank test, and multivariate proportional-hazards regression models. Haemorrhage was defined as a clinically symptomatic event with signs of acute bleeding on computed tomography or magnetic resonance brain imaging. Findings During mean follow-up of 8·5 months for the haemorrhage group and 11·9 months for the nonhaemorrhage group, haemorrhages occurred in 18 (13%) of the former patients and in three (2%) of the latter (p=0·0002). The annual risk of haemorrhage was 17·8% and 2·2%, respectively. In the multivariate regression model, the adjusted hazard ratio for haemorrhage at initial presentation was 13·9 (95% CI 2·6–73·8; p=0·002). Deep venous drainage (hazard ratio 4·1 [1·2–14·9], p=0·029) and male sex (9·2 [2·1–41·3], p=0·004) were also significantly associated with subsequent haemorrhage, but no significant association was found for age or AVM size. The annual rate of spontaneous haemorrhage was 32·6% for men and 10·4% for women in the haemorrhage group compared with 3·3% for men and 1·3% for women in the non-haemorrhage group. Among patients with haemorrhage at initial presentation, the risk of haemorrhage fell from 32·9% in year 1 to 11·3% in subsequent years (34·2% to 31·0% in men; 31·1% to 5·5% in women).
Departments of Neurology, Anesthesiology, Neurological Surgery, Radiology, and Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA (H Mast MD, W L Young MD, H-C Koennecke MD, R R Sciacca MD, A Osipov MD, J Pile-Spellman MD, L Hacein-Bey MD, H Duong MD, B M Stein MD, J P Mohr MD), and Department of Neurology, Universitätsklinikum Benjamin Franklin, Berlin, Germany (H-C Koennecke) Correspondence to: Dr Henning Mast, Stroke Unit, Neurological Institute, 710 West 168th Street, New York, NY 10032, USA (e-mail: [email protected])
Vol 350 • October 11, 1997
Interpretation In AVM, patients initially presenting with haemorrhage have a higher risk of subsequent bleeding than those presenting with other symptoms. The risk is higher in men than in women.
Lancet 1997; 350: 1065–68
Introduction Cerebral arteriovenous malformations (AVM) are the underlying cause of a small proportion of all strokes, but typically affect otherwise healthy young adults. The main goal of AVM treatment by modern endovascular techniques, microsurgery, and radiosurgery is the prevention of intracranial haemorrhage and its attendant brain injury. However, treatment itself carries a small but substantial risk, and the natural course of many AVM cases may be benign.1–3 Therefore, clinical, morphological, and haemodynamic risk predictors for untreated AVM are needed to enable better clinical decision-making. Retrospective analyses of selected series have suggested that the mode of initial clinical presentation of AVM may provide a marker for the subsequent risk of bleeding. Crawford and colleagues’ review4 suggested that patients who initially presented with haemorrhage had a greater rate of haemorrhage during the subsequent course than did those presenting with other symptoms. Subsequent reports on smaller5 or highly selected6 samples supported these observations. No study so far has investigated identifiable independent predictors for haemorrhage in the clinical course after AVM diagnosis—such as lesion size or drainage pattern—in unselected, untreated patients. We undertook such a study.
Patients and methods The Columbia-Presbyterian Medical Center AVM databank is a prospective database on all patients with cerebral AVM examined at the centre. The database includes demographic, clinical, laboratory, and treatment data since 1987. As a tertiary centre, specialising in cerebrovascular diseases and neurosurgical, endovascular, and radiosurgical treatment, our institution draws patients from the New York metropolitan area as well as from distant referral sites. The study was based on prospective enrolment between January, 1987, and May, 1996, of consecutive patients with retrospective assessment of initial AVM presentation. Table 1 shows baseline characteristics and initial AVM symptoms of the study sample. 142 patients initially presented with haemorrhage, defined as a clinically symptomatic event (sudden-onset headache, seizure, focal deficit, or a combination of these features) with signs of fresh bleeding on computed tomography or magnetic resonance brain imaging (haemorrhage group). The same criteria were used for the diagnosis of haemorrhage during the follow-up period. The remaining 139 patients initially presented with symptoms or signs unrelated to haemorrhage
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Haemorrhage group (n=142) Demography Mean (SD) age in years Male/female AVM characteristics Small size Deep drainage Infratentorial location Initial AVM presentation Haemorrhage Seizure† Chronic headache† Focal deficit† No symptoms† Unclassified†
Non-haemorrhage group (n=139)
Total (n=281)
35·9 (13·9) 71 (50%)/ 71 (50%)
33·6 (11·8) 62 (45%)/ 77 (55%)
34·8(12·9) 133 (47%)/ 148 (53%)
32 (23%) 42 (30%) 23 (16%)
10 (7%) 9 (6%) 7 (5%)
42 (15%) 51 (18%) 30 (11%)
142 (100%) ·· ·· ·· ·· ··
·· 75 (54%) 30 (22%) 14 (10%) 7 (5%) 13 (9%)
142 (51%) 75 (27%) 30 (11%) 14 (5%) 7 (3%) 13 (5%)
Data are number (%) of patients unless otherwise specified. *By Stein and Kader9 criteria: small AVM=maximum diameter 2·5 cm. †No signs of haemorrhage on imaging.
Table 1: Baseline characteristics and initial presentation in 281 prospectively enrolled consecutive patients with cerebral AVM (table 1) and served as the comparison group (non-haemorrhage group). Insufficient information was available for us to judge whether haemorrhage had occurred in an additional 15 cases excluded from the analysis. To ensure that the observation period did not include time under treatment, patients who underwent endovascular, surgical, or radiation procedures were censored (ie, withdrawn from lifetable analysis) at the start of any such therapy. Patients with one or more haemorrhages after initial presentation were censored at the first haemorrhage event. Kaplan-Meier life-tables were constructed for the frequency of AVM haemorrhage in the two groups during follow-up. The significance of group differences was assessed with the log-rank test. In addition, a multivariate proportional-hazards regression model, which included all modes of initial AVM presentation, was constructed. Previous studies have suggested that small AVM size and deep-venous AVM drainage are predictors of an increased risk of AVM haemorrhage.5,7,8 A further regression model (including AVM size and drainage, as well as the patient’s age and sex, and initial haemorrhage) tested the effect of these factors. AVM size definition followed the generally accepted Stein and Kader classification9 (table 1). Patients whose angiograms showed venous AVM drainage exclusively through the periventricular, Galenic, or cerebellar pathways were classified as having deep-venous drainage. The study was reviewed and approved by the ethics committee of the Columbia-Presbyterian Medical Center.
Results Haemorrhage during follow-up before start of treatment occurred in 18 (13%) patients in the haemorrhage group and in three (2%) of those without previous haemorrhage. The mean follow-up time was 8·5 months (range 0·1–96·4) in the haemorrhage group and 11·9 months (0·4–90·9) in the non-haemorrhage group. The annual rate of bleeding after initial AVM presentation was 17·8% in the haemorrhage group and 2·2% in the non-haemorrhage group. The annual rate of bleeding was higher for the first year (32·9%) than in subsequent years (11·3%) in the haemorrhage group. By contrast, in the non-haemorrhage group, the rate was 0% for the first year and 2·9% for subsequent years. Haemorrhage during follow-up was significantly associated with clinical presentation of haemorrhage as the initial symptom (hazard ratio 7·5 [95% CI 2·2–25·7]; p=0·0002, figure 1). Actuarial estimates of the cumulative 5-year risk of haemorrhage after initial 1066
Proportion remaining haemorrhage-free
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1·0 0·8 p = 0·0002 0·6 0·4 0·2
Non-haemorrhagic presentation (n=139) Haemorrhagic presentation (n=142)
0 0
1
2 3 4 Observation time (years)
5
Number in each group remaining at risk: 139 51 33
22
16
14
6
142 32 20 15 11 9 4 Figure 1: Kaplan-Meier life-table analysis of haemorrhage during clinical course before treatment according to initial presentation Two patients in the haemorrhage group and one in the nonhaemorrhage group who had haemorrhages after 5 years (81, 96, and 91 months) not shown.
presentation were 58% (SE 12) in the haemorrhage group and 10% (7) in the non-haemorrhage group. The regression model that included all modes of initial AVM presentation also showed a significant association of haemorrhage during follow-up with initial haemorrhage (6·7 [1·6–28·8]) but no significant effect was found for initial presentation with seizure (1·2 [0·3–5·4]), focal deficit (1·1 [0·4–3·1]), or headache (1·7 [0·6–4·5]). The effect of initial presentation with haemorrhage remained significant in the regression model that included age, sex, small AVM size, and deep drainage (table 2). In this model, significant associations with haemorrhage during follow-up were also found for male sex and exclusively deep-venous drainage. Small AVM size and age had no effect. Although initial presentation with haemorrhage was a significant risk factor in both sexes, the difference in risk of spontaneous haemorrhage between patients who did and did not present initially with haemorrhage was greater for men than for women (figure 2). Calculated annual event rates were 32·6% for men and 10·4% for women initially presenting with haemorrhage and 3·3% for men and 1·3% for women not initially presenting with haemorrhage. Among women in the haemorrhage group, the risk of spontaneous subsequent haemorrhage fell from 31·1% in year 1 to 5·5% in subsequent years; no similar trend was found among men (34·2% in year 1 and 31·0% in subsequent years). The comparison of the rates of haemorrhage in the two groups after year 1 (11·3 vs 2·9%) lacked statistical power
Haemorrhage as initial AVM presentation Age Male sex Small AVM size Deep drainage
Hazard ratio (95% CI)
p
13·9 (2·6–73·8) 1·2 (0·8–1·7) 9·2 (2·1–41·3) 1·3 (0·3–5·8) 4·1 (1·2–14·9)
0·002 0·421 0·004 0·725 0·029
Owing to missing data (undefined venous drainage pattern or undefined AVM size), 49 of 281 patients omitted from analysis.
Table 2: Results of regression analysis
Vol 350 • October 11, 1997
THE LANCET
Men 1·0 0·8 0·6
p = 0·0002
Proportion remaining haemorrhage-free
0·4 0·2 0
Women 1·0 p = 0·0076 0·8 0·6 0·4 0·2
Non-haemorrhagic presentation Haemorrhagic presentation
0 0
1
2 3 4 Observation time (years)
5
Figure 2: Kaplan-Meier life-table analysis of haemorrhage during clinical course before treatment according to initial presentation in men and women separately Haemorrhage group=71 men (one with haemorrhage at 96 months not shown) and 71 women (one with haemorrhage at 81 months not shown). Non-haemorrhage group=62 men and 77 women (one with haemorrhage at 91 months not shown).
(53 patients), but gave a hazard ratio of 3·14 (0·81–12·23; p=0·08). For 11 (52%) of the 21 patients with an AVM haemorrhage during follow-up, no associated neurological deficit was found. Among the ten with deficits, these were non-disabling or mildly disabling (Rankin scale scores <3, independence on Barthel score) in eight. The other two had disabling deficits (Rankin scale scores 3 and 5). None of the patients died. Follow-up haemorrhages were exclusively intraventicular in eight (38%) patients, intraparenchymatous in six (28%), subarachnoidal in two (10%), combined intraparenchymatous and intraventricular in four (19%), and undefined in one. Ten of the 11 patients without any neurological deficit had an exclusively intraventricular or subarachnoidal haemorrhage. Similarly, a focal neurological deficit related to the initial presentation haemorrhage was found in only 50 (35·2%) of the 142 haemorrhage-group patients; a disabling deficit was seen in only seven (4·9%) cases.
Discussion Our study shows a significantly higher risk of subsequent haemorrhage for AVM patients who initially present with haemorrhage than for patients with non-
Vol 350 • October 11, 1997
haemorrhagic presentation. This finding supports the idea of prognostically distinct AVM subgroups. Pooled data for 1860 reported AVM cases suggested that roughly 60% present with haemorrhage.10 In the few estimates available, the rate of haemorrhage in the course of untreated AVM was between 2% and 4% per year.4,11 A higher rate has been reported for patients initially presenting with haemorrhage than for patients with other diagnostic symptoms.4–6 Our findings extend these observations in a prospective study, which shows a larger annual risk of haemorrhage overall (10%), and an especially high rate in the group of patients initially presenting with haemorrhage (18%). We cannot exclude the possibility that referral patterns to our centre may have affected the findings. However, our data set includes all (seven) of the cases of AVM discovered in the population of about 250 000 who constitute the Northern Manhattan Stroke Study cohort.12 That population is not of the very large size needed to generate as many cases of AVM as we report here. Until such sufficiently large studies can be undertaken, our data and the smaller sets available may have to suffice for risk estimations in AVM patients. Other samples of patients with AVM had baseline characteristics similar to those of our patients.4–6,8,10,11 Thus, we believe that our sample is representative of the general AVM population. Some investigators have found no association of initial haemorrhage with further bleeding events in the subsequent clinical course. In a selected sample of 160 AVM cases followed up retrospectively over 24 years, Ondra and colleagues11 found no such association. Modern brain imaging and microsurgical techniques were not available for some of their cases, and a selection bias may have been introduced by choice of patients deemed surgically untreatable, thereby shifting cases with largesized and deeply located AVMs in eloquent brain areas into their sample. Most previous studies have reported haemorrhage as a single clinical entity, without giving details of severity; this approach implies that the event alone carries a uniform serious prognosis. Our data suggest the haemorrhagic event itself may be less serious than has been assumed. This finding would be of special interest had it been from a truly population-based study, but we cannot exclude the possibility of selection bias from the referral patterns in our cohort. Furthermore, our study does not provide data on the mortality of initial haemorrhages. Because of the available treatment options and current concerns about serious outcomes from haemorrhage, prospective natural-course studies in unselected samples of patients with AVM will continue to be difficult. Neither previously reported series nor our study can be taken as long-term prospective natural history investigations. Current clinical practice assumes a steady uniform long-term risk of AVM bleeding, but there are no observations to justify this notion. Our finding of a declining risk of haemorrhage over time in patients with haemorrhage at initial presentation may support the hypothesis of an improvement of the long-term risk of AVM haemorrhage.13,14 Therefore, the cumulative 5-year risk estimates yielded by our investigation have to be applied cautiously and may be viewed as a useful starting point for future studies. On the other hand, a 33% firstyear rate of haemorrhage alone may well be viewed as a substantial risk, justifying invasive treatment. 1067
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Previous work7,8,15 suggested an association of deep AVM drainage, small AVM size, and high feeding-artery pressure with initial presentation with haemorrhage, and implicated them as predictors of subsequent haemorrhage. Our data also show that deep-venous drainage is a strong and independent determinant of subsequent haemorrhage in the clinical course after AVM diagnosis. No such effect was found for small-sized AVMs but there were few small AVMs in our sample, so an association may not be detectable. The higher risk of haemorrhage for men than for women has not been reported previously and remains unexplained. The emerging set of clinical and morphological criteria defining AVM patients at higher risk of spontaneous bleeding should prove helpful in the decision-making process in individual patients and in the design of future outcome studies testing treatment effects.
References
Contributors
7
Henning Mast initiated and coordinated the formulation of the primary study hypothesis, discussed core ideas, designed the protocol particularly the documentation of clinical neurological data, and participated in data collection, analysis, and writing of the paper. William Young, the principal investigator of the Columbia-Presbyterian AVM Study Project, initiated the research, discussed core ideas, and participated in the protocol design, analysis and interpretation of the data, and writing of the paper. Hans-Christian Koennecke paticipated in the study design, data collection, and analysis, and edited the paper. Robert Sciacca initiated the research, participated in data documentation, analysed and interpreted the data, and contributed to writing of the paper. Andrei Osipov participated in the design and execution of the study particularly data collection, data documentation, and quality control, participated in the statistical analysis, and edited the paper. John Pile-Spellman initiated the reaserch, participated in data collection particularly on morphological aspects of AVM, discussed core ideas, and edited the paper. Lotfi Hacein-Bey and Hoang Duong participated in the design and execution (particularly neuroradiological aspects of AVM and morphological AVM classification), and edited the paper. Bennett Stein initiated the AVM research project, discussed core issues of the study and its design, collected data, and contributed to the paper. J P Mohr initiated the AVM research project, participated in the design of the study protocol, collected data, discussed core ideas and interpretation of the findings, and contributed to the paper.
1
2
3
4
5
6
8
9 10
11
12
13 14
15
Acknowledgments The study was supported by grants NS27713 and NS34949 from the National Institutes of Health.
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Marconi F, Parenti G, Puglioli M. Spontaneous regression of intracranial arteriovenous malformations. Surg Neurol 1993; 39: 385–91. McCormick WF, Rosenfield DB. Massive brain haemorrhage: a review of 144 cases and an examination of their causes. Stroke 1973; 4: 946–54. McCormick WF. Pathology of vascular malformations of the brain. In: Wilson CB, Stein BM, eds. Intracranial arteriovenous malformations. Baltimore: Williams & Wilkins, 1984: 44–63. Crawford PM, West CR, Chadwick DW, Shaw MDM. Arteriovenous malformations of the brain: natural history in unoperated patients. J Neurol Neurosurg Psychiatry 1986; 49: 1–10. Marks MP, Bracci P, Steinberg GK. Natural history of cerebral AVMs correlated with angiographic risk factors of hemorrhage. American Society of Neuroradiology 31st Annual Meeting, May 16–20, 1993; Vancouver, BC, Canada, 1993: 75. Pollock BE, Flickinger JC, Lunsford LD, Bissonette DJ, Kondziolka D. Factors that predict the bleeding risk of cerebral arteriovenous malformations. Stroke 1996; 27: 1–6. Kader A, Young WL, Pile-Spellman J, et al. The influence of hemodynamic and anatomic factors on hemorrhage from cerebral arteriovenous malformations. Neurosurgery 1994; 34: 801–08. Marks MP, Lane B, Steinberg GK, Chang PJ. Hemorrhage in intracerebral arteriovenous malformations: angiographic determinants. Radiology 1990; 176: 807–13. Stein BM, Kader A. Intracranial arteriovenous malformations. Clin Neurosurg 1992; 39: 76–113. Mast H, Mohr JP, Osipov A, et al. ‘Steal’ is an unestablished mechanism for the clinical presentation of cerebral arteriovenous malformations. Stroke 1995; 26: 1215–20. Ondra SL, Troupp H, George ED, Schwab K. The natural history of symptomatic arteriovenous malformations of the brain: a 24-year follow-up assessment. J Neurosurg 1990; 73: 387–91. Sacco RL, Kargman DE, Gu Q, Zamanillo MC. Race-ethnicity and determinants of intracranial atherosclerotic cerebral infarction: the Northern Manhattan Stroke Study. Stroke 1995; 26: 14–20. Fults D, Kelly DL. Natural history of arteriovenous malformations of the brain: a clinical study. Neurosurgery 1984; 15: 658–62. Itoyama Y, Uemura S, Ushio Y, et al. Natural course of unoperated arteriovenous malformations: study of 50 cases. J Neurosurg 1989; 71: 805–09. Spetzler RF, Hargraves RW, McCormick PW, Zabramski JM, Flom RA, Zimmerman RS. Relationship of perfusion pressure and size to risk of hemorrhage from arteriovenous malformations. J Neurosurg 1992; 76: 918–23.
Vol 350 • October 11, 1997
Risk of spontaneous haemorrhage after diagnosis of cerebral arteriovenous malformation
Henning Mast, William L Young, Hans-Christian Koennecke, Robert R Sciacca, Andrei Osipov, John Pile-Spellman, Lotfi Hacein-Bey, Hoang Duong, Bennett M Stein, J P Mohr
Summary Background A small proportion of strokes are caused by cerebral arteriovenous malformations (AVM). Treatment to prevent intracranial haemorrhage itself carries risks, and untreated AVM may in many cases have a good prognosis. We investigated the risk of subsequent symptomatic bleeding in the clinical course of AVM in patients with and without an initial haemorrhage. Methods 281 unselected, consecutive, prospectively enrolled patients with cerebral AVM were grouped according to their initial clinical presentation—142 presented with and 139 without haemorrhage. The frequency of AVM haemorrhages during the subsequent clinical course (before the start of endovascular, surgical, or radiation treatment) in the two groups was compared by means of Kaplan-Meier life-tables, log-rank test, and multivariate proportional-hazards regression models. Haemorrhage was defined as a clinically symptomatic event with signs of acute bleeding on computed tomography or magnetic resonance brain imaging. Findings During mean follow-up of 8·5 months for the haemorrhage group and 11·9 months for the nonhaemorrhage group, haemorrhages occurred in 18 (13%) of the former patients and in three (2%) of the latter (p=0·0002). The annual risk of haemorrhage was 17·8% and 2·2%, respectively. In the multivariate regression model, the adjusted hazard ratio for haemorrhage at initial presentation was 13·9 (95% CI 2·6–73·8; p=0·002). Deep venous drainage (hazard ratio 4·1 [1·2–14·9], p=0·029) and male sex (9·2 [2·1–41·3], p=0·004) were also significantly associated with subsequent haemorrhage, but no significant association was found for age or AVM size. The annual rate of spontaneous haemorrhage was 32·6% for men and 10·4% for women in the haemorrhage group compared with 3·3% for men and 1·3% for women in the non-haemorrhage group. Among patients with haemorrhage at initial presentation, the risk of haemorrhage fell from 32·9% in year 1 to 11·3% in subsequent years (34·2% to 31·0% in men; 31·1% to 5·5% in women).
Departments of Neurology, Anesthesiology, Neurological Surgery, Radiology, and Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA (H Mast MD, W L Young MD, H-C Koennecke MD, R R Sciacca MD, A Osipov MD, J Pile-Spellman MD, L Hacein-Bey MD, H Duong MD, B M Stein MD, J P Mohr MD), and Department of Neurology, Universitätsklinikum Benjamin Franklin, Berlin, Germany (H-C Koennecke) Correspondence to: Dr Henning Mast, Stroke Unit, Neurological Institute, 710 West 168th Street, New York, NY 10032, USA (e-mail: [email protected])
Vol 350 • October 11, 1997
Interpretation In AVM, patients initially presenting with haemorrhage have a higher risk of subsequent bleeding than those presenting with other symptoms. The risk is higher in men than in women.
Lancet 1997; 350: 1065–68
Introduction Cerebral arteriovenous malformations (AVM) are the underlying cause of a small proportion of all strokes, but typically affect otherwise healthy young adults. The main goal of AVM treatment by modern endovascular techniques, microsurgery, and radiosurgery is the prevention of intracranial haemorrhage and its attendant brain injury. However, treatment itself carries a small but substantial risk, and the natural course of many AVM cases may be benign.1–3 Therefore, clinical, morphological, and haemodynamic risk predictors for untreated AVM are needed to enable better clinical decision-making. Retrospective analyses of selected series have suggested that the mode of initial clinical presentation of AVM may provide a marker for the subsequent risk of bleeding. Crawford and colleagues’ review4 suggested that patients who initially presented with haemorrhage had a greater rate of haemorrhage during the subsequent course than did those presenting with other symptoms. Subsequent reports on smaller5 or highly selected6 samples supported these observations. No study so far has investigated identifiable independent predictors for haemorrhage in the clinical course after AVM diagnosis—such as lesion size or drainage pattern—in unselected, untreated patients. We undertook such a study.
Patients and methods The Columbia-Presbyterian Medical Center AVM databank is a prospective database on all patients with cerebral AVM examined at the centre. The database includes demographic, clinical, laboratory, and treatment data since 1987. As a tertiary centre, specialising in cerebrovascular diseases and neurosurgical, endovascular, and radiosurgical treatment, our institution draws patients from the New York metropolitan area as well as from distant referral sites. The study was based on prospective enrolment between January, 1987, and May, 1996, of consecutive patients with retrospective assessment of initial AVM presentation. Table 1 shows baseline characteristics and initial AVM symptoms of the study sample. 142 patients initially presented with haemorrhage, defined as a clinically symptomatic event (sudden-onset headache, seizure, focal deficit, or a combination of these features) with signs of fresh bleeding on computed tomography or magnetic resonance brain imaging (haemorrhage group). The same criteria were used for the diagnosis of haemorrhage during the follow-up period. The remaining 139 patients initially presented with symptoms or signs unrelated to haemorrhage
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Haemorrhage group (n=142) Demography Mean (SD) age in years Male/female AVM characteristics Small size Deep drainage Infratentorial location Initial AVM presentation Haemorrhage Seizure† Chronic headache† Focal deficit† No symptoms† Unclassified†
Non-haemorrhage group (n=139)
Total (n=281)
35·9 (13·9) 71 (50%)/ 71 (50%)
33·6 (11·8) 62 (45%)/ 77 (55%)
34·8(12·9) 133 (47%)/ 148 (53%)
32 (23%) 42 (30%) 23 (16%)
10 (7%) 9 (6%) 7 (5%)
42 (15%) 51 (18%) 30 (11%)
142 (100%) ·· ·· ·· ·· ··
·· 75 (54%) 30 (22%) 14 (10%) 7 (5%) 13 (9%)
142 (51%) 75 (27%) 30 (11%) 14 (5%) 7 (3%) 13 (5%)
Data are number (%) of patients unless otherwise specified. *By Stein and Kader9 criteria: small AVM=maximum diameter 2·5 cm. †No signs of haemorrhage on imaging.
Table 1: Baseline characteristics and initial presentation in 281 prospectively enrolled consecutive patients with cerebral AVM (table 1) and served as the comparison group (non-haemorrhage group). Insufficient information was available for us to judge whether haemorrhage had occurred in an additional 15 cases excluded from the analysis. To ensure that the observation period did not include time under treatment, patients who underwent endovascular, surgical, or radiation procedures were censored (ie, withdrawn from lifetable analysis) at the start of any such therapy. Patients with one or more haemorrhages after initial presentation were censored at the first haemorrhage event. Kaplan-Meier life-tables were constructed for the frequency of AVM haemorrhage in the two groups during follow-up. The significance of group differences was assessed with the log-rank test. In addition, a multivariate proportional-hazards regression model, which included all modes of initial AVM presentation, was constructed. Previous studies have suggested that small AVM size and deep-venous AVM drainage are predictors of an increased risk of AVM haemorrhage.5,7,8 A further regression model (including AVM size and drainage, as well as the patient’s age and sex, and initial haemorrhage) tested the effect of these factors. AVM size definition followed the generally accepted Stein and Kader classification9 (table 1). Patients whose angiograms showed venous AVM drainage exclusively through the periventricular, Galenic, or cerebellar pathways were classified as having deep-venous drainage. The study was reviewed and approved by the ethics committee of the Columbia-Presbyterian Medical Center.
Results Haemorrhage during follow-up before start of treatment occurred in 18 (13%) patients in the haemorrhage group and in three (2%) of those without previous haemorrhage. The mean follow-up time was 8·5 months (range 0·1–96·4) in the haemorrhage group and 11·9 months (0·4–90·9) in the non-haemorrhage group. The annual rate of bleeding after initial AVM presentation was 17·8% in the haemorrhage group and 2·2% in the non-haemorrhage group. The annual rate of bleeding was higher for the first year (32·9%) than in subsequent years (11·3%) in the haemorrhage group. By contrast, in the non-haemorrhage group, the rate was 0% for the first year and 2·9% for subsequent years. Haemorrhage during follow-up was significantly associated with clinical presentation of haemorrhage as the initial symptom (hazard ratio 7·5 [95% CI 2·2–25·7]; p=0·0002, figure 1). Actuarial estimates of the cumulative 5-year risk of haemorrhage after initial 1066
Proportion remaining haemorrhage-free
THE LANCET
1·0 0·8 p = 0·0002 0·6 0·4 0·2
Non-haemorrhagic presentation (n=139) Haemorrhagic presentation (n=142)
0 0
1
2 3 4 Observation time (years)
5
Number in each group remaining at risk: 139 51 33
22
16
14
6
142 32 20 15 11 9 4 Figure 1: Kaplan-Meier life-table analysis of haemorrhage during clinical course before treatment according to initial presentation Two patients in the haemorrhage group and one in the nonhaemorrhage group who had haemorrhages after 5 years (81, 96, and 91 months) not shown.
presentation were 58% (SE 12) in the haemorrhage group and 10% (7) in the non-haemorrhage group. The regression model that included all modes of initial AVM presentation also showed a significant association of haemorrhage during follow-up with initial haemorrhage (6·7 [1·6–28·8]) but no significant effect was found for initial presentation with seizure (1·2 [0·3–5·4]), focal deficit (1·1 [0·4–3·1]), or headache (1·7 [0·6–4·5]). The effect of initial presentation with haemorrhage remained significant in the regression model that included age, sex, small AVM size, and deep drainage (table 2). In this model, significant associations with haemorrhage during follow-up were also found for male sex and exclusively deep-venous drainage. Small AVM size and age had no effect. Although initial presentation with haemorrhage was a significant risk factor in both sexes, the difference in risk of spontaneous haemorrhage between patients who did and did not present initially with haemorrhage was greater for men than for women (figure 2). Calculated annual event rates were 32·6% for men and 10·4% for women initially presenting with haemorrhage and 3·3% for men and 1·3% for women not initially presenting with haemorrhage. Among women in the haemorrhage group, the risk of spontaneous subsequent haemorrhage fell from 31·1% in year 1 to 5·5% in subsequent years; no similar trend was found among men (34·2% in year 1 and 31·0% in subsequent years). The comparison of the rates of haemorrhage in the two groups after year 1 (11·3 vs 2·9%) lacked statistical power
Haemorrhage as initial AVM presentation Age Male sex Small AVM size Deep drainage
Hazard ratio (95% CI)
p
13·9 (2·6–73·8) 1·2 (0·8–1·7) 9·2 (2·1–41·3) 1·3 (0·3–5·8) 4·1 (1·2–14·9)
0·002 0·421 0·004 0·725 0·029
Owing to missing data (undefined venous drainage pattern or undefined AVM size), 49 of 281 patients omitted from analysis.
Table 2: Results of regression analysis
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Men 1·0 0·8 0·6
p = 0·0002
Proportion remaining haemorrhage-free
0·4 0·2 0
Women 1·0 p = 0·0076 0·8 0·6 0·4 0·2
Non-haemorrhagic presentation Haemorrhagic presentation
0 0
1
2 3 4 Observation time (years)
5
Figure 2: Kaplan-Meier life-table analysis of haemorrhage during clinical course before treatment according to initial presentation in men and women separately Haemorrhage group=71 men (one with haemorrhage at 96 months not shown) and 71 women (one with haemorrhage at 81 months not shown). Non-haemorrhage group=62 men and 77 women (one with haemorrhage at 91 months not shown).
(53 patients), but gave a hazard ratio of 3·14 (0·81–12·23; p=0·08). For 11 (52%) of the 21 patients with an AVM haemorrhage during follow-up, no associated neurological deficit was found. Among the ten with deficits, these were non-disabling or mildly disabling (Rankin scale scores <3, independence on Barthel score) in eight. The other two had disabling deficits (Rankin scale scores 3 and 5). None of the patients died. Follow-up haemorrhages were exclusively intraventicular in eight (38%) patients, intraparenchymatous in six (28%), subarachnoidal in two (10%), combined intraparenchymatous and intraventricular in four (19%), and undefined in one. Ten of the 11 patients without any neurological deficit had an exclusively intraventricular or subarachnoidal haemorrhage. Similarly, a focal neurological deficit related to the initial presentation haemorrhage was found in only 50 (35·2%) of the 142 haemorrhage-group patients; a disabling deficit was seen in only seven (4·9%) cases.
Discussion Our study shows a significantly higher risk of subsequent haemorrhage for AVM patients who initially present with haemorrhage than for patients with non-
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haemorrhagic presentation. This finding supports the idea of prognostically distinct AVM subgroups. Pooled data for 1860 reported AVM cases suggested that roughly 60% present with haemorrhage.10 In the few estimates available, the rate of haemorrhage in the course of untreated AVM was between 2% and 4% per year.4,11 A higher rate has been reported for patients initially presenting with haemorrhage than for patients with other diagnostic symptoms.4–6 Our findings extend these observations in a prospective study, which shows a larger annual risk of haemorrhage overall (10%), and an especially high rate in the group of patients initially presenting with haemorrhage (18%). We cannot exclude the possibility that referral patterns to our centre may have affected the findings. However, our data set includes all (seven) of the cases of AVM discovered in the population of about 250 000 who constitute the Northern Manhattan Stroke Study cohort.12 That population is not of the very large size needed to generate as many cases of AVM as we report here. Until such sufficiently large studies can be undertaken, our data and the smaller sets available may have to suffice for risk estimations in AVM patients. Other samples of patients with AVM had baseline characteristics similar to those of our patients.4–6,8,10,11 Thus, we believe that our sample is representative of the general AVM population. Some investigators have found no association of initial haemorrhage with further bleeding events in the subsequent clinical course. In a selected sample of 160 AVM cases followed up retrospectively over 24 years, Ondra and colleagues11 found no such association. Modern brain imaging and microsurgical techniques were not available for some of their cases, and a selection bias may have been introduced by choice of patients deemed surgically untreatable, thereby shifting cases with largesized and deeply located AVMs in eloquent brain areas into their sample. Most previous studies have reported haemorrhage as a single clinical entity, without giving details of severity; this approach implies that the event alone carries a uniform serious prognosis. Our data suggest the haemorrhagic event itself may be less serious than has been assumed. This finding would be of special interest had it been from a truly population-based study, but we cannot exclude the possibility of selection bias from the referral patterns in our cohort. Furthermore, our study does not provide data on the mortality of initial haemorrhages. Because of the available treatment options and current concerns about serious outcomes from haemorrhage, prospective natural-course studies in unselected samples of patients with AVM will continue to be difficult. Neither previously reported series nor our study can be taken as long-term prospective natural history investigations. Current clinical practice assumes a steady uniform long-term risk of AVM bleeding, but there are no observations to justify this notion. Our finding of a declining risk of haemorrhage over time in patients with haemorrhage at initial presentation may support the hypothesis of an improvement of the long-term risk of AVM haemorrhage.13,14 Therefore, the cumulative 5-year risk estimates yielded by our investigation have to be applied cautiously and may be viewed as a useful starting point for future studies. On the other hand, a 33% firstyear rate of haemorrhage alone may well be viewed as a substantial risk, justifying invasive treatment. 1067
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Previous work7,8,15 suggested an association of deep AVM drainage, small AVM size, and high feeding-artery pressure with initial presentation with haemorrhage, and implicated them as predictors of subsequent haemorrhage. Our data also show that deep-venous drainage is a strong and independent determinant of subsequent haemorrhage in the clinical course after AVM diagnosis. No such effect was found for small-sized AVMs but there were few small AVMs in our sample, so an association may not be detectable. The higher risk of haemorrhage for men than for women has not been reported previously and remains unexplained. The emerging set of clinical and morphological criteria defining AVM patients at higher risk of spontaneous bleeding should prove helpful in the decision-making process in individual patients and in the design of future outcome studies testing treatment effects.
References
Contributors
7
Henning Mast initiated and coordinated the formulation of the primary study hypothesis, discussed core ideas, designed the protocol particularly the documentation of clinical neurological data, and participated in data collection, analysis, and writing of the paper. William Young, the principal investigator of the Columbia-Presbyterian AVM Study Project, initiated the research, discussed core ideas, and participated in the protocol design, analysis and interpretation of the data, and writing of the paper. Hans-Christian Koennecke paticipated in the study design, data collection, and analysis, and edited the paper. Robert Sciacca initiated the research, participated in data documentation, analysed and interpreted the data, and contributed to writing of the paper. Andrei Osipov participated in the design and execution of the study particularly data collection, data documentation, and quality control, participated in the statistical analysis, and edited the paper. John Pile-Spellman initiated the reaserch, participated in data collection particularly on morphological aspects of AVM, discussed core ideas, and edited the paper. Lotfi Hacein-Bey and Hoang Duong participated in the design and execution (particularly neuroradiological aspects of AVM and morphological AVM classification), and edited the paper. Bennett Stein initiated the AVM research project, discussed core issues of the study and its design, collected data, and contributed to the paper. J P Mohr initiated the AVM research project, participated in the design of the study protocol, collected data, discussed core ideas and interpretation of the findings, and contributed to the paper.
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15
Acknowledgments The study was supported by grants NS27713 and NS34949 from the National Institutes of Health.
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Marconi F, Parenti G, Puglioli M. Spontaneous regression of intracranial arteriovenous malformations. Surg Neurol 1993; 39: 385–91. McCormick WF, Rosenfield DB. Massive brain haemorrhage: a review of 144 cases and an examination of their causes. Stroke 1973; 4: 946–54. McCormick WF. Pathology of vascular malformations of the brain. In: Wilson CB, Stein BM, eds. Intracranial arteriovenous malformations. Baltimore: Williams & Wilkins, 1984: 44–63. Crawford PM, West CR, Chadwick DW, Shaw MDM. Arteriovenous malformations of the brain: natural history in unoperated patients. J Neurol Neurosurg Psychiatry 1986; 49: 1–10. Marks MP, Bracci P, Steinberg GK. Natural history of cerebral AVMs correlated with angiographic risk factors of hemorrhage. American Society of Neuroradiology 31st Annual Meeting, May 16–20, 1993; Vancouver, BC, Canada, 1993: 75. Pollock BE, Flickinger JC, Lunsford LD, Bissonette DJ, Kondziolka D. Factors that predict the bleeding risk of cerebral arteriovenous malformations. Stroke 1996; 27: 1–6. Kader A, Young WL, Pile-Spellman J, et al. The influence of hemodynamic and anatomic factors on hemorrhage from cerebral arteriovenous malformations. Neurosurgery 1994; 34: 801–08. Marks MP, Lane B, Steinberg GK, Chang PJ. Hemorrhage in intracerebral arteriovenous malformations: angiographic determinants. Radiology 1990; 176: 807–13. Stein BM, Kader A. Intracranial arteriovenous malformations. Clin Neurosurg 1992; 39: 76–113. Mast H, Mohr JP, Osipov A, et al. ‘Steal’ is an unestablished mechanism for the clinical presentation of cerebral arteriovenous malformations. Stroke 1995; 26: 1215–20. Ondra SL, Troupp H, George ED, Schwab K. The natural history of symptomatic arteriovenous malformations of the brain: a 24-year follow-up assessment. J Neurosurg 1990; 73: 387–91. Sacco RL, Kargman DE, Gu Q, Zamanillo MC. Race-ethnicity and determinants of intracranial atherosclerotic cerebral infarction: the Northern Manhattan Stroke Study. Stroke 1995; 26: 14–20. Fults D, Kelly DL. Natural history of arteriovenous malformations of the brain: a clinical study. Neurosurgery 1984; 15: 658–62. Itoyama Y, Uemura S, Ushio Y, et al. Natural course of unoperated arteriovenous malformations: study of 50 cases. J Neurosurg 1989; 71: 805–09. Spetzler RF, Hargraves RW, McCormick PW, Zabramski JM, Flom RA, Zimmerman RS. Relationship of perfusion pressure and size to risk of hemorrhage from arteriovenous malformations. J Neurosurg 1992; 76: 918–23.
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