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III. Natural history

The mean AVM risk of bleeding varies in literature from 2 to 4% per year [15, 20, 31, 36, 78, 79, 101, 108]. The mortality risk is 1% per year [20, 78, 79, 101, 108]. After a first bleeding, the risk of re-bleeding rises to 6 to 18% in the first year, then goes back to the previous risk in the years that follow [20, 59, 103]. However, Ondra et al. [79] and Crawford et al. [13] demonstrated that 6 months after a bleed, the risk of hemorrhage is the same for patients with prior hemorrhage and for patients who have never had a hemorrhage.

The lifetime risk of bleeding is between 17 to 90% [78, 101]. Lehecka et al. [50] proposed that the percentage risk to have a fatal bleeding from an untreated AVM during a life time may be roughly estimated as : (90 - age in years)%.

After each AVM bleed there is a mortality rate of 5 to 15% and an additional 20% to 30% risk of serious morbidity [26, 89]. Some series describes a bad functional evolution in even 30 to 56% of patients [5, 33, 73].

Not all AVMs present the same risk of bleeding, and some factors are related to a greater risk. Hernesniemi et al. [31] in a study of 238 patients with a mean follow-up period of 13.5 years found an annual risk of hemorrhage from AVMs of 2.4%. They indicated as risk factors predicting subsequent AVM hemorrhage in univariate analysis : young age, previous rupture, deep and infratentorial locations, and exclusively deep venous drainage. In addition, they indicated as independent risk factors according to multivariate models : previous rupture, large AVM size, and infratentorial and deep locations.

Other risks factors indicated mentioned in literature [20] :
 Intranidal aneurysm : 15% of all AVMs are associated to aneurysms that may be located in the feeding arteries (flow aneurysms), in arteries not related to the irrigation of the AVM or in the nidus (intranidal). Redekop et al. [87] reviewed 632 cases of AVMs diagnosed through angiography and found an incidence of 5.5% of intranidal aneurysms, 11.2% of flow aneurysms and 0.8% of aneurysms not related to the malformation. It is still unknown if there is a difference among those locations when reporting hemorrhages. Some authors [6] recommend to first treat the aneurysm in asymptomatic patients. They say that after resecting the AVM there is a supposed greater risk of aneurysm rupture due to a temporary increase in the pressure of the feeding artery. Other authors consider that asymptomatic flow aneurysms do not need to be treated because after the excision of the AVM these aneurysms spontaneously disappear.
 Ventricular or paraventricular AVM ;
 Stenosis of the draining vein (the risk of bleeding should be directly proportional to the degree of stenosis) ;
 Number of draining veins (the risk of bleeding is inversely proportional to the number of draining veins, probably due to the increase of flow and turbulence in the case of a smaller number of draining channels [66], being of a higher risk in cases of a single draining vein) ;

Small AVMs are also listed as a risk factor according to some authors. This is a very controversial aspect, so Hernesniemi et al. [31] in his series pointed out that large AVMs have a higher risk of bleeding. We believe that there is an important confounding aspect, because the only clinical manifestation of the small AVM is related to bleeding, so one may have the wrong impression that they are more prone to bled.

AVMs that never bled without bleeding risk factors may present a lower risk of bleeding, such as 1% a year whereas those with bleeding risk factors that also never bled present a higher risk of bleeding of 8% a year. On the other hand, in the case of AVMs that already bled and that present bleeding risk factors, the re-bleeding rate in the first year can reach 35% [20, 99].

Autopsy studies conclude that only 12% of all AVMs became symptomatic in a lifetime, what may be related to the lack of data on the history of bleeding in such type of study [60, 61].

The “A Randomized Trial of Un-ruptured Brain AVMs” (ARUBA) is a trial that aims to assess the outcomes of patients with un-ruptured AVMs randomized to medical management alone (ie, pharmacological therapy for neurological symptoms as needed) versus medical management with interventional therapy (ie, neurosurgery, embolisation, or stereotactic radiotherapy, alone or in combination) [70, 71]. The primary outcome was the time to the composite endpoint of death or symptomatic stroke ; and the primary analysis was by the intention to treat. [71]

The original plan was to randomize 800 patients with un-ruptured brain AVMs and determine whether or not the risks of treatment outweighed the risks of conservative management over 5 years. However, the randomization was stopped prematurely by the data safety monitoring board with a mean follow up of 33 months and 223 patients (114 assigned to interventional therapy and 109 to medical management) because of the superiority of the medical management group. [71]

The demographic characteristics were similar between the two groups. However the risk of death or stroke was significantly lower in the medical management group (11 patients – 10.1%) than in the interventional therapy group (35 patients – 30.7%). [71] However, as the findings of this study did not consider the degree of AVM, it should not be used to guide management in these patients.

The ARUBA trial in its 33 months of follow up concluded that medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke in patients with un-ruptured brain arteriovenous malformations. [71] They will continue its observational phase to establish whether the disparities will persist over an additional 5 years of follow-up.

Stapf et al. [100] and Starke et al. [101] analyzed preview data from ARUBA and observed that Spetzler Martin grade I and II demonstrates similar outcomes in medical and surgical group, but significantly worse outcomes in grade III and IV AVM in the surgical group. Besides this some of ARUBA’s limitations are highlighted by Starke et al [101] and include the short follow up period ; small sample size ; the study is not powered to evaluate the treatment effect by an individual modality and the great heterogeneity of the treatment and experience in each center. Besides, these and many other methodological inconsistences and bias were predicted by Cockroft et al. [12] and put in to check ARUBA’s value [69].

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