Unruptured Cerebral Arteriovenous Malformations

8 Unruptured Cerebral Arteriovenous Malformations

Marie-Christine Brunet, Evan Luther, David J. McCarthy, and Robert M. Starke

Abstract

The management of unruptured cerebral arteriovenous malformations (AVMs) is a difficult topic that remains controversial. The decision to manage these lesions conservatively or intervene depends largely on patient’s age, presentation, lesion size, and location. Even with ideal circumstances for intervention, some argue for conservative management. There remains insufficient knowledge regarding the lifetime hemorrhage risk of AVMs, and studies supporting conservative therapy over intervention often provide only early results. To manage these patients appropriately, it is imperative to understand the implications and limitations of these studies, AVM hemorrhage risk factors, and risks and benefits of various treatment options.

Keywords: arteriovenous malformations, embolization, radiosurgery, risk management

8.1 Goals

1. Analyze the literature regarding the natural history of arteriovenous malformations (AVMs).

2. Assess studies that investigate treatment of unruptured AVMs versus observation.

3. Briefly review AVM treatment options, risks, and success rates.

8.2 Case Example

8.2.1 History of Present Illness

A 41-year-old previously healthy female presents for initial evaluation complaining of progressively worsening right-sided headaches, right orbital pain, and “visual difficulties.”

Past medical history: Denies any prior relevant history.

Past surgical history: None.

Family history: Denies history of any vascular disease.

Social history: Nonsmoker, drinks socially.

Review of systems: As per the above.

Neurological examination: With detailed examination, she

was found to have a left-homonymous hemianopsia.

Imaging studies: See figures.

▶ Fig. 8.1 (a,b) Brain cerebral angiogram demonstrated a Spetzler-Martin grade IV right temporo-occipital AVM with a maximum diameter of 40.1 mm, primarily fed by the middle cerebral artery with an associated 8.0 x 6.9 mm perinidal aneurysm and both superficial and deep venous drainage.

8.2.2 Treatment Plan

The patient agreed to treatment of the symptomatic AVM. The recommendation was made for neoadjuvant embolization of the deep feeder to ease the surgical removal of the AVM. Postoperative angiogram seen in ▶ Fig. 8.2a, b demonstrates no residual AVM.

Fig. 8.1 Brain angiogram (a,b) showing a Spetzler-Martin grade IV right arteriovenous malformation (AVM) with a maximum diameter of 40.1 mm, primarily fed by the middle cerebral artery, with an associated 8.0 x 6.9 mm perinidal aneurysm (arrow in b).

Fig. 8.2 (a,b) Six-month follow-up angiogram of the brain demonstrating complete arteriovenous malformation (AVM) obliteration.

8.2.3 Follow-up

The patient did very well after the embolization and microsurgical resection. As expected she had initial worsening of her homonymous hemianopsia. At her 6-month follow-up visit, angiogram demonstrated complete AVM obliteration (▶ Fig. 8.2b) as well as subjective and objective improvement of her homonymous hemianopsia. Only a trace homonymous hemianopsia residual was noted on physical examination, which was not perceptible to patient. She returned to work fully functional.

8.3 Case Summary

1. What would you consider the rupture risk of the unruptured AVM in this patient?

Our knowledge, with regard to the natural risk of AVM rupture, is limited to prospective and retrospective cohorts. Later in this chapter, we will review the largest of these studies and the strengths and limitations of each one. The most recent meta-analyses report the annual rupture risk for unruptured brain AVMs to be 1.3 to 2.2%, but the overall literature supports an annual risk of 1 to 4%.!,²

2. What patient factors would you consider when deciding on your recommendations for observation or treatment of these unruptured cerebral AVMs?

a) Age

Since it is believed that the annual risk of hemorrhage for AVMs remains constant, younger patients have a higher lifetime risk of hemorrhage; therefore, there is more precedent for treatment. Conversely, younger patients may have to live longer with deficits incurred due to complications of an intervention. It is imperative to weigh the risks of treatment versus conservative management as we will discuss later.

In elderly patients with low-risk lesions, it may be better to intervene as opposed to observation since increasing age has been identified as a possible risk factor for rupture in some meta-analysis. Other studies failed to reach the same conclusion, and this may be due to lead time, selection, and follow-up bias.¹^,³^,⁴^,⁵^,⁶

b) Patient symptoms

Other than hemorrhage, brain AVMs may present with a variety of complaints and neurological alterations. Often unruptured AVMs can cause focal or secondary seizures, with a reported 5-year risk of seizure estimated around 8%.⁷^,⁸ Younger age, temporal location, cortical involvement, and nidus diameter > 3 cm increase the risk of seizure.³^,⁸ It is not certain that intervention reduces seizure risk; however, a meta-analysis reported that microsurgery had the highest seizure reduction rate (78.3%), followed by stereotactic radiosurgery (SRS) (62.8%), and embolization (49.3%).⁹

Unruptured AVMs may present with headaches and other variable symptoms, such as focal weakness or visual alterations. There is no evidence showing that AVM intervention reduces headaches.¹⁰ However, in our case example, the patient had almost complete resolution of symptoms.

3. What AVM factors would you consider when deciding on your recommendations for observation or treatment?

a) Prior hemorrhage

While our patient never suffered a hemorrhage, the largest risk factor for future hemorrhage of an AVM is a prior hemorrhage.³

b) AVM location

It has been shown that deep and infratentorial AVM locations are independent risk factors for hemorrhage.¹^,²^,³^,⁴^,⁵^,⁶

c) Various angioarchitecture characteristics

There are several AVM angioarchitectural characteristics that increase its risk of hemorrhage. In short, venous outflow limited to deep venous structures, associated arterial aneurysms (pre- or intranidal), single draining veins, venous varices, and venous stenosis are all considered independent risk factors.²^,³^,⁶^,¹¹^,¹²^,¹³^,¹⁴ Our patient had a large perinidal aneurysm, increasing her risk for future hemorrhage.

4. How would you follow this AVM with or without treatment? There are several methods for following treated AVMs with imaging studies: digital subtraction angiography, computed tomography angiography, or magnetic resonance angiography. Depending on the method of treatment, intensive imaging follow-up may be necessary. It has been reported that magnetic resonance angiography follow-up offers similar accuracy in lesions greater than 1 cm.¹⁵ All patients should have an angiogram at some point to ensure complete obliteration. In this instance, we elected to follow up with digital subtraction angiography.

8.4 Level of Evidence

Patient’s age, symptoms, and AVM grade: Given the Spetzler-Martin grade IV AVM, surgical treatment poses significant risks; however, since the patient was young, had neurological deficit, and a perinidal aneurysm, we elected to proceed with intervention (Class lib, Level of Evidence B).

Risk of future hemorrhage: The patient was young and had a large perinidal aneurysm (Class Ha, Level of Evidence A).

Treatment: Due to the large size of the lesion, we decided against SRS treatment (Class I, Level of Evidence B). We decided to perform preoperative embolization to decrease the morbidity and mortality associated with the surgery resection (Class Ha, Level of Evidence B).

Follow-up of aneurysm: We followed this lesion with digital subtraction angiography (Class I, Level of Evidence B).

8.5 Hemorrhage Risk in Unruptured AVMs

8.5.1 Natural History

The natural history of unruptured brain AVMs remains a controversial topic. Our current understanding is based on studies analyzing the clinical course of untreated patients; however, there has yet to be a prospective clinical study that aims to describe rupture risk in a population that is without selection bias.³ Based on the available data, it is generally accepted that the annual risk of rupture in untreated unruptured AVMs is between 1 and 4%.³^,⁴^,⁶^,¹⁶^,¹⁷^,¹⁸

In 1990, Ondra et al published a retrospective series on the natural history of 166 patients with known brain AVMs who did not undergo surgical treatment. The follow-up rate was very high (96%), and the patients were monitored for a mean of 24 years. This cohort demonstrated a 4% annual rupture risk and 1% annual mortality rate. However, these results were based on composite outcomes that included previously ruptured

brain AVMs, leaving the true rate of hemorrhage for unruptured AVMs unknown.¹⁸

More recently, Halim et al performed a prospective analysis of 790 patients with brain AVMs diagnosed between 1961 and 2001. Beginning with the date of initial AVM diagnosis (including AVMs presenting with hemorrhage), patients were followed until subsequent rupture, initiation of treatment, or last available follow-up appointment.⁴ The dropout rate was similar to Ondra’s study, but follow-up time was significantly less. In the patient cohort who did not present with rupture, the annual rupture risk was found to range from 0.3 to 4% and decreased over time. In 2006, Stapf et al published a similar prospective study on 622 patients with brain AVMs. Again, the patients were followed from initial diagnosis until onset of treatment.⁶ With a mean follow-up time of 2.3 years, the annual rupture risk was 1.3%, similar to that of Halim’s cohort. The short follow-up times are limitations to both studies, but they did provide some further insight into the natural history of unruptured AVMs. In 2008, Hernesniemi et al published another prospective study that followed 238 patients with brain AVMs for a mean follow-up period of 13.5 years. During this period, they found that the average rupture risk of unruptured AVMs was 1.6%.⁵ These studies all indicated that the annual rupture risk for well-selected unruptured AVMs might in fact be lower than previously described. More recently, several meta-analyses have reported an annual rupture risk of 1.3 to 2.2% for unruptured AVMs.¹² All of these studies suffer from selection bias and suggest that rupture risk is dependent on a number of identifiable clinical and morphological features.

8.5.2 Predictors of Hemorrhage

The most important and consistently demonstrated clinical characteristic that has been found to increase the risk of hemorrhage in AVMs is rupture at initial presentation.³ Increasing age has also been identified as a possible risk factor for rupture in some meta-analyses, but this has not been confirmed in other studies.¹^,³^,⁴^,⁵^,⁶ Anatomic features that have been identified in meta-analyses and observational cohorts as independent risk factors for hemorrhage are deep and infratentorial locations.¹^,²^,³^,⁴^,⁵^,⁶ Several studies have also been performed to analyze the various angioarchitectural characteristics that contribute to hemorrhage in unruptured AVMs. These included venous outflow limited to deep venous structures, associated arterial aneurysms (pre- or intranidal), single draining veins, venous varices, and venous stenosis.²^,³^,⁶^,¹¹^,¹²^,¹³^,¹⁴ AVM size has also been identified as a possible predictor, but results have been inconsistent.

8.6 Management: Conservative versus Intervention

In 2010, Ross and Al-Shahi Salman conducted a systematic review to identify randomized clinical studies comparing outcomes following different unruptured AVM management.⁷ No completed study met their inclusion criteria; however, they identified the ARUBA study¹⁷ as the only ongoing study investigating this important question.

MohrJP, Parides MK, StapfC, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. The Lancet 2014;383:614-621.

From 2007 to 2013, Mohr et al screened 1,740 patients for trial eligibility, ultimately randomizing 226 patients to either intervention (n = 116) or medical management (n = 110). Patients were assessed for eligibility if they were older than 18 years, had neurovascular image confirmed AVM, and no prior hemorrhage or treatment attempt. Interventions included radiosurgery, microsurgery, endovascular intervention, or any combination of these procedures. Primary outcome was time until any-cause death or symptomatic stroke, defined as any new neurological focal deficit, headache, or seizure with associated image findings (blood or low-density ischemic lesions). Secondary outcome was functional dependency at 5 years, defined as modified Rankin scale of 2 or higher.¹⁹

Originally designed to enroll 800 patients, sample size was reduced to 400 patients following slow patient accrual in the first 18 months. The ARUBA trial was prematurely halted when conservative management reached a predetermined efficacy, for the prevention of stroke or death, in an interim analysis. A total of 223 patients were randomized, with a mean follow-up of 33.3 months (IQR 16.3-49.8 months). The final statistical analysis was conducted with 53% of the anticipated data (of the 400-patient sample size). Under both intention-to-treat and as-treated analyses, investigators found that conservative management had a significantly lower risk for primary outcome event than intervention. In addition, the risk of death or neurological disability was significantly lower in the conservatively managed cohort. Further analysis demonstrated that primary event occurrence remained similar regardless of Spetzler-Martin (S-M) grade in the medically managed arm; however, it occurred more frequently in patients with an S-M grade II or III in the intervention arm.

The ARUBA study reached the controversial conclusion that the risk of death or stroke in patients with unruptured AVMs was higher for patients undergoing intervention versus conservatively managed for 33 months of follow-up. In 2017, Magro et al conducted a systematic review of all the published critiques and comments involving ARUBA and identified 31 published critiques.²⁰ While the ARUBA trial addressed a paramount question, the trial design and possible biases limited the external validity of the study. Regarding study design, the academic community has critiqued the study’s end points, selection criteria, and absent treatment arm standardization.

Many stated that the end points were “soft” and favored conservative management.²⁰ The primary end point of the trial labeled a stroke as any postoperative new or worsening neurological focal deficit, headache, or seizure with associated imaging findings (blood or low-density ischemic lesions). Practitioners argue that a headache or an initial worsening of symptoms with contrast leakage often transiently occurs following an endovascular intervention. This argument was supported by an unusually high primary outcome incidence of 30.7% in the intervention arm, most of which occurred during the first 6 months following intervention. Furthermore, the AVM obliteration rate was not reported—a relevant statistic considering that partial AVM embolization does not necessarily reduce hemorrhage risk.³ Authors did not specify if endovascular embolization was performed with cyanoacrylate-based liquid embolic agents or Onyx, each of which have different success rates.³

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