Precision Medicine in Brain Arteriovenous Malformation Management: Arteries Steal the Show but Veins May Hold the Crystal Ball

Zammar, Samer G. MD; Hamade, Youssef J. MD; Aoun, Rami J. MD, MPH; El Tecle, Najib E. MD, MS; El Ahmadieh, Tarek Y. MD; Lall, Rohan R. MD; Taub, Zachary D.; Swanson, Kristin R. PhD; Chandler, James P. MD; Bendok, Bernard R. MD, MSCI

doi: 10.1227/01.neu.0000457193.02158.c9
Science Times

Northwestern University Feinberg School of Medicine, Chicago, Illinois

Article Outline

Hemorrhage remains the most dreaded complication related to brain arteriovenous malformations (bAVMs). Despite cohort studies demonstrating a 2% to 4% annual risk of hemorrhage for these lesions, individualized hemorrhage risk can vary widely.1 In these studies, multiple risk factors, both patient and AVM specific,2 have been found to have varying degrees of association with hemorrhage risk. Of these factors, prior hemorrhage, deep venous drainage, deep location, ventricular or periventricular location, posterior fossa location, single draining vein, and nidus size have all been associated with a higher risk of rupture.3-7 There are, however, scarce physiological theories and hypotheses that link these characteristics to the risk of rupture. It is possible that all or some of these characteristics are merely associations with another factor that may be the true culprit. This factor could be venous outflow obstruction.

To address this interesting question, Sahlein et al8 retrospectively analyzed 122 bAVMs in 121 patients who underwent superselective microcatheter angiography. With the intention to look for associated causes of bleeding, the authors characterized the bAVMs on the basis of the location, depth, nidus size, flow physiology, arterial supply, associated aneurysms, pial collaterals, border morphology (compact vs diffuse), presence of moyamoya changes, venous drainage characteristics, and bAVM eloquence as defined by Spetzler and Martin. Univariate analysis showed an association between hemorrhage risk and deep supratentorial location (P = .004), exclusive deep venous drainage (P = .009), and absence of pial-pial collateral from major arterial distributions (P = .01). bAVMs associated with aneurysms and those with venous outflow stenosis showed a trend toward significance with respect to hemorrhage (both P = .08). Furthermore, the authors found that bAVMs with a single draining vein were more likely to hemorrhage than those with ≥2 draining veins (P = .004). This latter outcome has been well reported in the literature3,9-11 and could be explained by the fact that bAVMs with a higher number of draining veins may have lower flow impedance and thus less risk for hemorrhage. The authors tested this hypothesis by conducting a second univariate analysis on bAVMs that have multiple draining veins and some venous stenosis that can potentially mimic the physiology of bAVMs with a single draining vein. The results showed that bAVMs with ≥2 draining veins were more likely to hemorrhage if they had a venous outflow stenosis compared with those without stenosis (P = .02). The authors here imply a physiological equivalency between a single draining vein and multiple draining veins with ≥1 stenosis. This finding lends some credence to the causal relationship of venous outflow obstruction and bAVM hemorrhage risk. The article suggests that some bAVM characteristics that have been shown to be associated with hemorrhage but have no obvious physiological rationale for this association (such as small bAVM size, deep venous drainage, absence of pial-pial collaterals, and deep supratentorial location) may in fact be “innocently” associated with the true culprit: venous outflow obstruction. It is notable that about 70% of bAVMs with these features had 1 draining vein or the physiological equivalent as defined by the authors. Lastly, the adjusted odds ratio for hemorrhage was highest for 1 draining vein, followed by the presence of venous stenosis and finally the presence of an aneurysm, as shown by the multivariate logistic regression model (all statistically significant; Table).

This thought-provoking article makes a daring leap from a body of knowledge based on association to a physiological hypothesis that starts to point an accusatory finger at venous outflow obstruction as an important causal factor for bAVM hemorrhage risk. Health care is evolving rapidly toward precision medicine. Precision medicine requires individualized risk assessment and tailoring of treatment recommendations. The heterogeneity of AVM anatomy, natural history, treatment suitability, and treatment modalities calls for a dedicated focus on using precision medicine research techniques to refine our approach to this potentially devastating disease. Growing insights from magnetic resonance imaging hemodynamic techniques,12 molecular imaging, and vascular biology promise to shed further light on AVM pathophysiology.13 These growing insights may one day allow sophisticated individualized risk assessment so that AVMs can be treated with the highest possible quality of care.

Back to Top | Article Outline

REFERENCES

1. Stapf C, Mast H, Sciacca RR, et al.. Predictors of hemorrhage in patients with untreated brain arteriovenous malformation. Neurology. 2006;66(9):1350–1355.
2. Abecassis IJ, Xu DS, Batjer HH, Bendok BR. Natural history of brain arteriovenous malformations: a systematic review. Neurosurg Focus. 2014;37(3):E7.
3. Nataf F, Meder JF, Roux FX, et al.. Angioarchitecture associated with haemorrhage in cerebral arteriovenous malformations: a prognostic statistical model. Neuroradiology. 1997;39(1):52–58.
4. Stapf C, Mohr JP, Sciacca RR, et al.. Incident hemorrhage risk of brain arteriovenous malformations located in the arterial borderzones. Stroke. 2000;31(10):2365–2368.
5. Crawford PM, West CR, Chadwick DW, Shaw MD. Arteriovenous malformations of the brain: natural history in unoperated patients. J Neurol Neurosurg Psychiatry. 1986;49(1):1–10.
6. Khaw AV, Mohr JP, Sciacca RR, et al.. Association of infratentorial brain arteriovenous malformations with hemorrhage at initial presentation. Stroke. 2004;35(3):660–663.
7. Yamada S, Takagi Y, Nozaki K, Kikuta K, Hashimoto N. Risk factors for subsequent hemorrhage in patients with cerebral arteriovenous malformations. J Neurosurg. 2007;107(5):965–972.
8. Sahlein DH, Mora P, Becske T, et al.. Features predictive of brain arteriovenous malformation hemorrhage: extrapolation to a physiologic model. Stroke. 2014;45(7):1964–1970.
9. Albert P, Salgado H, Polaina M, Trujillo F, Ponce de Leon A, Durand F. A study on the venous drainage of 150 cerebral arteriovenous malformations as related to haemorrhagic risks and size of the lesion. Acta Neurochir (Wein). 1990;103(1-2):30–34.
10. Miyasaka Y, Yada K, Ohwada T, Kitahara T, Kurata A, Irikura K. An analysis of the venous drainage system as a factor in hemorrhage from arteriovenous malformations. J Neurosurg. 1992;76(2):239–243.
11. Shi X, Wang Z, Yu C. An analysis of the correlation between angiographic and clinical findings in cerebral arteriovenous malformations. Chin Med Sci J. 1993;8(1):35–37.
12. Ansari SA, Schnell S, Carroll T, et al.. Intracranial 4D flow MRI: toward individualized assessment of arteriovenous malformation hemodynamics and treatment-induced changes. AJNR Am J Neuroradiol. 2013;34(10):1922–1928.
13. Bendok BR, El Tecle NE, El Ahmadieh TY, et al.. Advances and innovations in brain arteriovenous malformation surgery. Neurosurgery. 2014;74(suppl 1):S60–S73.
Copyright © by the Congress of Neurological Surgeons