Risks of Combined Therapies

Introduction

While the goals and outcomes of the individual components of multimodality therapy are reviewed elsewhere, the risk profile of multimodality therapy is worth discussing, both broken down into the unique risks associated with each treatment strategy and in a holistic review of the risks of combination therapy. Multimodality therapy emerged as a way of increasing efficacy in a stepwise fashion for curing otherwise hard-to-treat intracranial arteriovenous malformations (iAVMs). In 1995, the first seminal series on multimodality treatment of iAVMs was published. The authors reported on a total of 32 patients. Twenty-two had surgically accessible, high-risk lesions in the brainstem and thalamus underwent microsurgery, and in half of these cases the AVMs were treated preoperatively with endovascular embolization. Ten more patients were deemed to have surgically inaccessible lesions and underwent radiosurgery after embolization.

This work, which laid the foundation for two and a half decades of progress, demonstrated a dramatic reduction in morbidity and mortality. There were no deaths, and the morbidity rate (for these otherwise high-risk brainstem and thalamic AVMs) was 9%. These results have prompted many others to address AVMs with multimodality therapy. As of 2016, the 100 most-cited documents in iAVM literature have a cumulative 25,823 citations, representing well-known, influential papers in iAVM research. Yet, recent surveys of neurosurgeons and neurointerventionalists demonstrate significant discordance in clinicians’ opinions on the management of AVMs. The specialty of the physician who first sees a patient with an iAVM often determines management. An opportunity therefore exists to better understand and apply the complementary risk and efficacy profile of each modality to standardize and maximize their combined application.

Embolization Followed by Resection

Preoperative, staged embolization is becoming a more common tool in AVM management ( Fig. 21.1 ). Although microsurgical resection remains the standard for definitive cure of most iAVMs, embolization can enhance the efficacy and safety when utilized as a preoperative adjunct. Rather than elevating risk, preoperative embolization has been shown to reduce operative time and blood loss with no difference in neurological outcome or complications. (The safety profile of endovascular monotherapy is reviewed elsewhere, and embolization is addressed in this chapter only as part of multimodality therapy.) In some cases, iAVMs that initially had high Spetzler-Martin grades have been shown to convert to lower-grade lesions through the elimination of deep feeding arteries and choroidal vessels, decreasing the active nidus, and the elimination of nidal aneurysms; thus inoperable lesions may occasionally be converted to operable ones. Presurgical embolization has been shown in some cohorts to reduce the risk of intraoperative hemorrhage and facilitate intraoperative decision-making, as embolized vessels can be used as easily identifiable landmarks intraoperatively. This is particularly true if adjunctive embolization successfully reduces the residual AVM supply to a single arterial distribution.

In terms of additive risk, embolization followed by surgery has been shown in large cohorts to carry a risk of symptomatic stroke or death that is roughly equivalent to that of surgery or radiosurgery alone (5% vs 7%, 8%). As with all neurointerventional procedures, any step in the embolization process—from gaining arterial access to achieving hemostasis—involves risks to the patient, including groin complications (hematoma or dissection), contrast reactions, and nephrotoxicity. Periprocedural complications that are particularly relevant to iAVM embolization include intracerebral hemorrhage and ischemia/infarction leading to transient or permanent neurological deficits. Periprocedural hemorrhage can be induced by technical factors, such as arterial injury either from microcatheters or during catheter retrievals, or with inadvertent sacrifice of outflow veins and subsequent elevation of intranidal pressures. These complications can be severe, necessitating immediate craniotomy and AVM resection. Therefore it is crucial to have a surgical plan in consideration when embolizing iAVMs, even in a staged approach. There is little evidence in the literature to address the periprocedural risk of operating on iatrogenically ruptured iAVMs, but late-stage embolizations should be planned with an eye to the potential contingency of immediate resective surgery in the setting of rupture or venous stasis.

The most frequently reported complications of endovascular therapy for iAVMs are stroke, hemorrhage, and mortality. Treatment failure is also common. In a large series of 306 patients undergoing a total of more than 500 embolization sessions over nearly 20 years, the AVM obliteration rate in those who underwent embolization with curative intent was 31%. There were 62 complications in 56 patients (18%). The complications included 8 deaths (2.6%) and 25 permanent and 23 transient neurological deficits; the rate of death or any permanent disabling neurological morbidity was 3.9%. A smaller, recently published study of 55 patients treated exclusively with Onyx (Medtronic, Minneapolis, MN) for preoperative embolization resulted in a complication rate of 13%, though with no increased risk of mortality, suggesting that Onyx may be a safer alternative to use in these cases. Prospective registry or trial efforts will continue to add to these data.