Editorial. Management of high-grade brain arteriovenous malformations: the current state of knowledge

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  • 1 Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
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We read with great interest the retrospective cohort study by Li et al.1 that evaluated the long-term outcomes of patients with Spetzler-Martin grade IV–V brain arteriovenous malformation (bAVM) managed at a single high-volume center. Eighty-two patients with high-grade ruptured or unruptured bAVMs who received follow-up for a mean of approximately 5 years were studied to compare functional outcome, obliteration rate, seizure control, and risk of hemorrhage between those who received conservative management and those who underwent intervention (microsurgery, embolization, or hybrid surgery). This is one of the largest single-center series dedicated to high-grade bAVM. It showed that intervention had an advantage for avoidance of long-term severe disability (modified Rankin Scale score > 3) in comparison with observation (1.7% vs 18.2%). Intervention also demonstrated better seizure control and protection from subsequent hemorrhage, with hybrid surgery resulting in less intraoperative blood loss than microsurgery.

From a statistical standpoint, there are important considerations worth mentioning. Multivariable analysis is often utilized in retrospective studies to adjust for confounding variables, such as lesion location/size/diffuseness, associated aneurysms, rupture at presentation, baseline functional status, and medical comorbidities. Although no multivariable analysis was conducted, the baseline characteristics of the conservative and intervention cohorts were well balanced, indicating low risk of bias from confounding. Regarding the main outcome of interest, only 5 patients had severe disability at the end of follow-up (4 in the conservative management group and 1 in the intervention group), which makes it difficult to draw reliable conclusions. This is best evidenced by the wide confidence interval of the odds ratio (0.008–0.727). Overall, one would expect the study to be underpowered for the detection of outcome differences, especially for more subtle findings and those of the subgroup analyses (such as variations among treatment strategies or subtypes of grade IV bAVM). It is crucial to interpret the findings of the current study and to plan future relevant studies with this limitation in mind.

The final results of A Randomized trial of Unruptured Brain Arteriovenous Malformations (ARUBA) were recently published, documenting outcomes over 5 years of follow-up.2 The trial included a total of 22 unruptured high-grade Spetzler-Martin grade IV bAVMs, for which medical management was superior for prevention of all-cause mortality or symptomatic stroke (5/8 patients [63%] vs 2/15 [13%], p < 0.05). The conclusions of ARUBA were challenged, and multiple subsequent analyses that utilized high-quality registries of ARUBA-eligible patients were able to show that, in general, the outcomes of careful patient selection and long-term follow-up favored interventional therapy.3,4 Most of these studies focused on evaluating low- and intermediate-grade bAVMs, for which intervention affords the most favorable risk-benefit ratio.

The study by Li et al. is a significant contribution to the literature because it puts forth data suggesting that judicious patient selection for therapy—even for high-grade bAVM patients and specifically those with progressive neurological deficits or at high risk for recurrent hemorrhage—may result in better outcomes than conservative management. A thorough understanding of the natural disease history is necessary whenever management decisions are considered,5,6 which may be challenging to assess in a retrospective setting because many patients may be treated early in the disease course. The study by Laakso et al. provided a focused natural history analysis of 63 ruptured and unruptured high-grade bAVMs, showing that patients with these lesions have higher cumulative risks of hemorrhage and, when they do rupture, higher morbidity and mortality rates than patients with bAVM in general; these findings are most likely due to the large size and eloquence of these high-grade lesions.7 Although one may hesitate to subject patients with high-grade bAVMs to the risks of treatment, the perilous natural history of these lesions must also be acknowledged, especially for younger patients with an elevated cumulative lifetime risk.

This analysis touched on the safety and efficacy of embolization, when administered as a single-modality palliative strategy and as an adjunct to resection in the setting of a combined hybrid embolization–microsurgical procedure. With respect to stand-alone embolization (n = 19), complete embolization was achieved in 5.3% of patients and perioperative and follow-up hemorrhage occurred in 15.8% (the highest incidence of all treatment groups). This corroborates the findings of Pérez-Alfayate et al., who reported an overall complication rate of 65% for 22 patients with high-grade bAVM who underwent embolization and a periprocedural hemorrhage rate of 42%.8 Such findings suggest that the role of stand-alone embolization in the management of high-grade bAVM is extremely limited. Concerning the use of embolization as an adjunct to microsurgery, the hybrid approach achieved a statistically significant benefit in terms of long-term complete obliteration and intraoperative blood loss, as well as a trend toward increased protection against subsequent hemorrhage. These patients also achieved the highest absolute rates of favorable seizure control and best long-term mean functional status scores when compared with those patients who underwent stand-alone embolization or microsurgery, but those differences were not statistically significant.

The use of a hybrid operating room with both endovascular and microsurgical capabilities has emerged as a new interventional strategy that was utilized by the authors in this study. An earlier comparative analysis by authors from the same institution of 38 cases of high-grade bAVM treated with hybrid versus stand-alone microsurgery indicated relatively worse outcomes in the patients who underwent the hybrid approach, but these findings were not statistically significant. However, as expected, the lesions treated with the hybrid approach had relatively more complex morphological and angioarchitectural characteristics, which may have confounded the results.9 Another recent analysis of 1-stage hybrid treatment by Song et al. showed that 1-year functional outcomes were comparable between high-grade (n = 14) and low-grade (n = 40) bAVMs.10 More studies are needed to reconcile these conflicting findings. From the standpoint of external validity, a third of the patients in the study by Li et al. were treated with the hybrid strategy, which requires specific expertise and infrastructure for effective implementation.

When contemplating management strategies for high-grade bAVM, surgeons must realize that not all grade IV and V AVMs are comparable. In a study of 53 patients with high-grade bAVMs treated with microsurgery, perforating arterial supply and involvement of the corticospinal tract independently predicted worse short-term and long-term functional outcomes, and larger nidus size (cutoff 6.8 cm) predicted a significantly higher rate of postoperative intracerebral hemorrhage.10 Larger sample sizes may help determine whether specific subtypes of high-grade bAVMs may benefit from certain forms of intervention. The current study did not include patients treated with stereotactic radiosurgery. In an international multicenter study of 233 patients with high-grade bAVMs, single-session radiosurgery demonstrated very limited efficacy with favorable outcome achieved in only a minority of those with unruptured lesions.11

In conclusion, Li and colleagues have provided a meaningful contribution to the growing literature on the management of high-grade bAVMs, as well as encouragement for further in-depth study of the utility of multimodal intervention for the management of these challenging lesions. Moving forward, because randomized trials are unlikely to be conducted given ethical and practical considerations, two approaches can serve to bridge remaining knowledge gaps. One involves leveraging multicenter collaborations to establish large cohorts that are both representative and powered to pinpoint outcome differences among various lesion subtypes and treatment approaches. The second represents consolidation of published work into pooled estimates by conducting systematic reviews and meta-analyses.

Disclosures

The authors report no conflict of interest.

References

  • 1

    Li N, Yan D, Li Z, et al. Long-term outcomes of Spetzler-Martin grade IV and V arteriovenous malformations: a single-center experience. Neurosurg Focus. 2022;53(1):E12.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Mohr JP, Overbey JR, Hartmann A, et al. Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial. Lancet Neurol. 2020;19(7):573581.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Feghali J, Huang J. Updates in arteriovenous malformation management: the post-ARUBA era. Stroke Vasc Neurol. 2020;5(1):3439.

  • 4

    Feghali J, Huang J. "ARUBA” aftermath: subsequent studies and current management of unruptured arteriovenous malformations. World Neurosurg. 2019;128:374375.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Feghali J, Yang W, Xu R, et al. R2eD AVM score. Stroke. 2019;50:17031710.

  • 6

    Hung AL, Yang W, Jiang B, et al. The effect of flow-related aneurysms on hemorrhagic risk of intracranial arteriovenous malformations. Neurosurgery. 2019;85(4):466475.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Laakso A, Dashti R, Juvela S, Isarakul P, Niemelä M, Hernesniemi J. Risk of hemorrhage in patients with untreated Spetzler-Martin grade IV and V arteriovenous malformations: a long-term follow-up study in 63 patients. Neurosurgery. 2011;68(2):372378.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Pérez-Alfayate R, Grasso G, Pérez CF, Arias-Díaz J, Sallabanda-Díaz K. Does endovascular treatment with curative intention have benefits for treating high-grade arteriovenous malformation versus radiosurgery? Efficacy, safety, and cost-effectiveness analysis. World Neurosurg.2021;149:e178e187.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Wang M, Lin F, Qiu H, Cao Y, Wang S, Zhao J. Comparison of endovascular embolization plus simultaneous microsurgical resection vs. primary microsurgical resection for high-grade brain arteriovenous malformations. Front Neurol. 2021;12:756307.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Song J, Li P, Tian Y, et al. One-stage treatment in a hybrid operation room to cure brain arteriovenous malformation: a single-center experience. World Neurosurg.2021;147:e85e97.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Patibandla MR, Ding D, Kano H, et al. Stereotactic radiosurgery for Spetzler-Martin Grade IV and V arteriovenous malformations: an international multicenter study. J Neurosurg. 2018;129(2):498507.

    • Crossref
    • Search Google Scholar
    • Export Citation

Illustration from Agosti et al. (E5). Used with permission of Mayo Foundation for Medical Education and Research. All rights reserved.

  • 1

    Li N, Yan D, Li Z, et al. Long-term outcomes of Spetzler-Martin grade IV and V arteriovenous malformations: a single-center experience. Neurosurg Focus. 2022;53(1):E12.

    • Search Google Scholar
    • Export Citation
  • 2

    Mohr JP, Overbey JR, Hartmann A, et al. Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial. Lancet Neurol. 2020;19(7):573581.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Feghali J, Huang J. Updates in arteriovenous malformation management: the post-ARUBA era. Stroke Vasc Neurol. 2020;5(1):3439.

  • 4

    Feghali J, Huang J. "ARUBA” aftermath: subsequent studies and current management of unruptured arteriovenous malformations. World Neurosurg. 2019;128:374375.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Feghali J, Yang W, Xu R, et al. R2eD AVM score. Stroke. 2019;50:17031710.

  • 6

    Hung AL, Yang W, Jiang B, et al. The effect of flow-related aneurysms on hemorrhagic risk of intracranial arteriovenous malformations. Neurosurgery. 2019;85(4):466475.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Laakso A, Dashti R, Juvela S, Isarakul P, Niemelä M, Hernesniemi J. Risk of hemorrhage in patients with untreated Spetzler-Martin grade IV and V arteriovenous malformations: a long-term follow-up study in 63 patients. Neurosurgery. 2011;68(2):372378.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Pérez-Alfayate R, Grasso G, Pérez CF, Arias-Díaz J, Sallabanda-Díaz K. Does endovascular treatment with curative intention have benefits for treating high-grade arteriovenous malformation versus radiosurgery? Efficacy, safety, and cost-effectiveness analysis. World Neurosurg.2021;149:e178e187.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Wang M, Lin F, Qiu H, Cao Y, Wang S, Zhao J. Comparison of endovascular embolization plus simultaneous microsurgical resection vs. primary microsurgical resection for high-grade brain arteriovenous malformations. Front Neurol. 2021;12:756307.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Song J, Li P, Tian Y, et al. One-stage treatment in a hybrid operation room to cure brain arteriovenous malformation: a single-center experience. World Neurosurg.2021;147:e85e97.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Patibandla MR, Ding D, Kano H, et al. Stereotactic radiosurgery for Spetzler-Martin Grade IV and V arteriovenous malformations: an international multicenter study. J Neurosurg. 2018;129(2):498507.

    • Crossref
    • Search Google Scholar
    • Export Citation

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