Chapter 93 Imaging Evaluation and Endovascular Treatment of Vasospasm

James Chen, Sudhir Kathuria, Dheeraj Gandhi

The phenomenon of cerebral vasospasm following aneurysmal subarachnoid hemorrhage (aSAH) was first described in the 1950s by Ecker and Riemenschneider,¹ and substantial contributions have been made in subsequent decades to the clinical and pathophysiologic understanding of this debilitating condition. The traditional belief has been that subarachnoid blood products trigger vasospasm of the proximal, large-caliber cerebral vessels, which consequently leads to impaired cerebral perfusion and eventual infarction of the affected tissue. Modern investigations of this phenomenon, which has been termed delayed cerebral ischemia (DCI), have further implicated distal microvascular disease² and dysregulated proliferation of smooth muscle and endothelial cells in its pathophysiology.^3,⁴ While the complete picture of its pathogenesis remains to be fully elucidated, there is strong evidence that the presence of severe vasospasm correlates with the development of DCI and subsequent cerebral infarcts. Prompt diagnosis and treatment of vasospasm prior to the onset of permanent ischemic damage are therefore essential to improving survival and preventing secondary loss of neurologic function in the aSAH patient population.⁵

Historically, the most common cause of mortality following initial hemorrhage from aSAH was rebleeding. Advancements in surgical and endovascular techniques and a general trend toward more aggressive, early repair of aneurysm have led to a decrease in the incidence of this complication.⁶ DCI from vasospasm has thus emerged as the most common cause of secondary morbidity and death. From literature and clinical experience, this reversible narrowing of cerebral vessels typically occurs between 3 and 14 days⁷^–⁹ following initial hemorrhage, with a peak incidence around day 7.¹⁰ Up to 70% of patients demonstrate angiographically visible vasospasm within this time window, but only 20% to 30% of these cases develop clinical evidence of cerebral ischemia and consequently require acute therapy.^7,^8,^11,¹² Of symptomatic patients, up to 50% suffer devastating neurologic deficits or death as a result of clinically significant vasospasm, highlighting the importance of prompt diagnosis and therapeutic management.^9,¹³

To assess which patients are at highest risk of developing vasospasm, various groups have suggested clinical factors, including Hunt and Hess grading and characteristics of the subarachnoid clot on computed tomography (CT) (i.e., initial presence, volume, density, and duration) that associate with an increased risk of vasospasm.^6,^7,⁸ Other clinical variables, including young patient age, poor neurologic grade, greater-than-normal thickness of the subarachnoid clot, intraventricular or intracerebral hemorrhage, and history of smoking, have been associated with the development of more severe vasospasm.^8,^11,¹² While these considerations can aid in the care of aSAH patients, no comprehensive prediction algorithm exists to determine which patients will suffer DCI. Therefore, there continues to be no substitute for vigilant clinical monitoring and careful decision making by an experienced, multidisciplinary care team to prevent or limit the neurologic injury from vasospasm.¹⁴

Clinical Assessment

Frequent neurologic evaluations play an essential role in the diagnosis of DCI. Common symptoms that should raise alarm include the development of confusion, delirium, decreased consciousness, or new, focal neurologic deficits. Symptoms can emerge acutely or fulminantly, and nonspecific signs such as headache or increasing neck stiffness can sometimes be the only notable findings during the onset of cerebral ischemia. Furthermore, alternative etiologies for altered mental status and focal neurologic deficits, including hydrocephalus, systemic infection, seizures, or ongoing delirium, must be ruled out. A meaningful neurologic examination may not be achievable in patients who have suffered severe neurologic impairment or are comatose at baseline. In such cases, imaging studies inevitably play a larger role in monitoring for symptomatic vasospasm.

Diagnostic Imaging

Transcranial Doppler Ultrasonography

Transcranial Doppler (TCD) ultrasonography has been widely employed as the first-line modality for monitoring cerebral vasospasm in aSAH patients (Fig. 93-1). It is noninvasive, inexpensive, and easily performed at the bedside, making it particularly appropriate for daily evaluations. The sensitivity of TCD is highest for vasospasm in the proximal middle cerebral artery (MCA) but decreases in other vascular territories.¹⁵ It also varies depending on the adequacy of vessel insonation.¹⁶ The diagnostic value of TCD comes from its high specificity—detection of normal flow velocities can effectively exclude the presence of vasospasm.¹⁷ It is thus an excellent modality for initial patient triage.

FIGURE 93-1 A patient with recent SAH demonstrated fluctuating right lower extremity weakness and aphasia. A, A screening color Doppler study reveals elevated flow velocities in the left MCA, suggestive of moderate vasospasm. B, A digital subtraction angiogram, with a anteroposterior view of left internal carotid injection, shows mild to moderate caliber reduction of the M2 branches (arrows). C, Given the predominantly distal location and moderate severity of the vasospasm, this patient was treated with IA nicardipine alone. The anteroposterior view of the left internal carotid injection following slow infusion of 5 mg of nicardipine demonstrates the augmented caliber of M2 branches and the improved filling of distal cortical branches.

Noncontrast Head CT

For patients with changes in clinical exam or TCD findings, noncontrast head CT should be performed before any subsequent interventions are considered. This modality offers a rapid survey for infarctions in the territory of suspected vasospasm and rules out other etiologies of neurologic deterioration, including hydrocephalus and rehemorrhage. The identification of developing infarcts has important implications for subsequent treatment decision making, because the restoration of flow to these areas typically provides minimal recovery of neurologic function and can potentially lead to further decline as a result of reperfusion hemorrhage.^18,¹⁹

Computed Tomography Angiography and Perfusion

Computed tomography angiography (CTA) and computed tomography perfusion (CTP) imaging have undergone significant advancements in recent years and have emerged as effective modalities for triaging vasospasm patients toward endovascular therapy (Fig. 93-2). CTA has been shown to be highly accurate for detection of severe vasospasm (more than 50% luminal reduction) and has excellent negative predictive value.^20,²¹ The severity of vasospasm can be overestimated in certain vascular territories, and metallic artifacts from coils or clips can hinder the assessment of nearby territories. Despite these limitations, CTA provides an informative and practical assessment of cerebral vessel caliber in patients with concerning symptoms. The recent addition of CTP scans to the vasospasm imaging armamentarium has allowed insight into the hemodynamic implications of CTA findings. Stereotypical patterns of perfusion abnormality can indicate the presence of either reversible ischemia, which should be addressed promptly to maximize penumbral recovery, or irreversible ischemia, which is a contraindication to aggressive therapy. This distinction is essential for the appropriate triage of patients toward endovascular therapy, because the treatment of infarcted territories potentially leads to further morbidity. A combined, multimodality, CT-based approach has been implemented at many institutions, allowing acquisition of conventional CT, CTA, and CTP images in one setting. This protocol is well suited for aSAH patients for whom lengthy transport or imaging studies may be unfeasible. Clinicians need to be wary of radiation exposure when ordering repeated CT studies; there have been reports of associated sequelae in the medical literature and lay press.²²

FIGURE 93-2 A 44-year-old male, 9 days status post-SAH and embolization, developed increasing drowsiness and stopped following commands. Doppler ultrasound was suspicious for severe vasospasm. A, Initial head CT demonstrating diffuse SAH. Note a more focal hemorrhage in the interpeduncular cistern. B, An irregular basilar tip aneurysm was the cause of the SAH. C, This was embolized, with complete occlusion of the aneurysm. D, MRI at this time showed small watershed infarcts. A perfusion image shown here reveals bilateral elevation in mean transit time, asymmetrically more so in the right hemisphere (arrow).FIGURE 93-2, cont’dA CTP study in the sagittal (E) and coronal (F) planes confirms the perfusion abnormalities. Small matched defects on the cerebral blood flow (arrow) and cerebral blood volume maps in the watershed zones suggest small foci of irreversible ischemic injury. However, there is a large area of penumbra (arrowheads) that could be prevented with early intervention. G, A CTA shaded-surface image confirms bilateral MCA (right greater than left) and A1 spasm (arrows).

Magnetic Resonance Angiography and Perfusion-Weighted Magnetic Resonance Imaging

Magnetic resonance angiography and perfusion-weighted magnetic resonance imaging (MRI) have been used for detecting vasospasm (Fig. 93-2) but have failed to achieve wider adoption for vasospasm imaging due to logistical impracticability of MRI in acutely sick patients.

Digital Subtraction Angiography

Digital subtraction angiography (DSA) remains the gold standard for evaluation of cerebral vasospasm and provides the foundation for all endovascular treatments. It is highly sensitive and specific for detection of proximal, as well as distal, lesions and provides real-time assessment of hemodynamic alterations. Because it is a costly and resource-intensive procedure with a small risk of procedural complications, patients should undergo noninvasive imaging first before receiving DSA.

Medical Therapies for Cerebral Vasospasm

Although the scope of this chapter is endovascular management for vasospasm, we must emphasize that medical therapy remains the first-line and mainstay treatment for a majority of patients. Hemodynamic therapy via induced hypervolemia, hypertension, and hemodilution (triple-H therapy) has achieved widespread use, and studies have demonstrated efficacy in improving cerebral perfusion, as well as clinical outcomes.²³ Patients who do not respond to this treatment or who cannot tolerate sufficient periods of hyperdynamic therapy due to underlying medical comorbidities are candidates for endovascular intervention.

Overview of Endovascular Therapies for Cerebral Vasospasm

The goal of endovascular therapy for symptomatic cerebral vasospasm is to restore blood flow to ischemic parenchyma and salvage the penumbra region (Figs. 93-1, 93-3, and 93-4). These interventions are not the first-line treatment due to inherent procedural risks and intensive resource requirements, but when performed in appropriately selected patients, they can produce excellent angiographic and clinical outcomes.

FIGURE 93-3 Improvements in endovascular semicompliant balloon technology have resulted in safer, more controlled angioplasty procedures. A, Left vertebral angiography in a patient with moderate spasm of the basilar artery and severe spasm of the bilateral P1 and P2 segments is demonstrated. B, This was treated with balloon angioplasty of all involved segments. This image shows an inflated Hyperform balloon in the right P2 segment. C, Note the markedly improved appearance of the basilar artery and the posterior cerebral arteries. There is some residual spasm in the cortical segments, but it was no longer restricting flow.

FIGURE 93-4 Combined therapy (IA verapamil and balloon angioplasty) of vasospasm. A, An initial CT scan shows diffuse SAH and a left frontal intraparenchymal hematoma. The cause of this SAH was believed to be a left-sided posterior communicating artery aneurysm, shown on anteroposterior (B) and lateral (C) projections. The aneurysm was clipped. In B, the left A1 segment is hypoplastic (arrow). D, The patient experienced symptomatic vasospasm. An angiogram reveals severe vasospasm of the left M1 segment and moderate spasm of the supraclinoid ICA.FIGURE 93-4, cont’dE, The left MCA and distal ICA were treated with angioplasty with good result. The A1 segment was intentionally not angioplastied since it was a congenitally hypoplastic vessel. Angioplasty of a hypoplastic vessel should be avoided to prevent the risk of vessel rupture. F, Restoration of anterior cerebral artery (ACA) perfusion was addressed from the contralateral, dominant right A1. This right ICA angiogram reveals vasospasm of the distal right A1 and proximal A2 segments (arrows). G, The spastic right A1 segment was treated with balloon angioplasty. A subsequent angiogram shows improved vessel caliber of the target segment and more robust filling of the distal ACA branches.

The two classes of current endovascular therapies are intra-arterial (IA) vasodilator infusion and transluminal balloon angioplasty (TBA), which can be used in isolation or combination and are chosen depending on the location of vasospasm. Proximal lesions are ideally treated through mechanical balloon angioplasty with optional, complementary IA infusion, whereas distal lesions should be addressed with IA infusion alone.

IA Vasodilator Infusion

IA vasodilator infusions have been employed widely for the pharmacologic treatment of cerebral vasospasm, but the efficacy and duration of these agents remains modest. For distal vasospasm that cannot be readily accessed by mechanical angioplasty devices, IA vasodilator infusions nonetheless provide an important means to improve blood flow and prevent permanent ischemic damage (Fig. 93-1). Anecdotal reports have also suggested the use of IA vasodilator infusion as an adjunct to angioplasty to reduce the vasomotor tone of the vessel and potentially decrease the subsequent risk of acute vessel rupture during balloon dilation (Fig. 93-4).

Papaverine

The first pharmacologic vasodilator that was employed broadly for treatment of cerebral vasospasm was papaverine, an alkaloid of the opium group with a half-life of 2 hours that acts as a nonspecific vasodilator by increasing cyclic adenosine monophosphate levels in smooth muscle cells.^24,²⁵ Studies examining the efficacy of the drug demonstrated angiographic improvement in 75% of cases, but modest clinical improvements were achieved in only 25% to 52% of patients.^19,^26,²⁷ Furthermore, these improvements were often transient, and some patients required multiple treatments, which were associated with worsened complication profiles.²⁵ Described complications include raised intracranial pressure (ICP), seizures, hypotension, transient brain stem depression, worsening vasospasm, monocular blindness if infusion is performed proximal to the ophthalmic artery origin, and gray matter injury by direct neurotoxicity.^18,^27,²⁸ The combination of these risks with the papaverine’s relatively short duration of action have led to the replacement of this drug by calcium channel blockers (CCBs) for IA treatment of vasospasm in modern practice.

Calcium Channel Blockers

As a class, CCBs have been met with the greatest recent investigational interest because of their excellent safety profiles and consistent efficacy. Their implementation as IA agents was logical, because there has been extensive experience with intravenous administration of these drugs to patients before and after definitive aneurysm therapy. Mechanistically, the benefit of these drugs have traditionally been attributed to inhibition of voltage-gated calcium channels in smooth muscle cells, but evidence that patients can demonstrate a positive clinical response without corresponding improvements to angiographic vasospasm have alluded to the presence of indirect benefits, such as neuroprotective effects.²⁹ Verapamil, nimodipine, and nicardipine have been the most studied of the CCBs, but randomized, controlled trials examining the use of these drugs for treatment of vasospasm remain to be conducted, and their use toward this application still remains off-label. As such, the optimal doses, infusion rates, and retreatment intervals remain to be definitively studied and vary substantially between groups.

Verapamil is a phenylalkylamine CCB with a half-life of approximately 7 hours. Preliminary studies have yielded mixed results, with some groups reporting angiographic and clinical improvement ³⁰ while others have been unable to demonstrate statistically significant effects.³¹ The ambiguity of these data may be due to the lack of quantified analysis and blinded radiographic review among some of these studies.³² The appropriate dose to achieve therapeutic effects remains uncertain. On one hand, groups have reported the doses as high as 41 mg per procedure³³ but Feng et al. demonstrated increased vessel diameter in 44% of patients and neurologic improvement in 29% with only 3 mg per procedure.³⁰ The appropriate time course of administration also remains to be elucidated—most studies to date have employed bolus infusion strategies, but it has been suggested that prolonged infusions may offer greater clinical benefit. Albanese et al. recently examined the efficacy of long-term IA infusion (average of 7.8 hours) with an average dose per vessel of 164.6 mg in 12 patients and reported improved vessel caliber in 89% of treated vessels, with favorable clinical outcome at 8 to 12 months in 73% of patients.³⁴ As optimization of the treatment protocol improves through additional research, the potential for further improvements in angiographic and clinical outcomes is optimistic.

Nimodipine is a dihydropyridine CCB with a half-life of approximately 8 to 9 hours that works through mechanisms similar to those of verapamil and possesses a similar safety profile. It has not been available for use in the United States but has been adopted in Europe and Australasia. Biondi et al. reported clinical improvement 19 of 25 patients (76%) in the first 24 hours following IA nimodipine infusion.³⁵ At 3 to 6 months follow-up, 18 patients (72%) had a favorable clinical outcome. Successful dilation of infused vessels, however, occurred in only 13 out of 30 (43%) of procedures, so the results raise some uncertainty as to whether improvements in vessel caliber were truly responsible for the positive outcomes. Doses of up to 3 mg per vascular territory were used (for a total of 1-5 mg per session) at a rate of 1 mg over 10 to 15 minutes to minimize hypotension. No episodes of increased ICP or other complications were noted. The use of continuous nimodipine infusion for vasospasm that is refractory to bolus treatment has been reported in a series of 9 patients by Wolf et al.³⁶ The authors used a 2 mg per hour or 2 mg every 30 minutes for a three-times-daily infusion schedule and showed improvements in CTP patterns and positive long-term clinical outcomes in 3 patients (33%). However, another 3 patients (33%) died from refractory vasospasm, so further investigations are necessary before definitive recommendations for the use of continuous infusions can be made.

Nicardipine is a dihydropyridine CCB that is more selective for vascular smooth muscle than for cardiac smooth muscle and possesses a half-life of approximately 16 hours (Fig. 93-1). In the series by Badjatia et al., 44 vessels were treated in 18 patients at doses of 0.5 to 6 mg per vessel.³⁷ DSA and TCD demonstrated reductions in vasospasm in all patients, and clinical improvement was observed in 42% of patients. Although the drug was generally well tolerated, 4 patients suffered transient increases in ICP and 1 had a persistent increase that necessitated termination of nicardipine infusion. In a subsequent paper, Tejada et al. reported a series of 20 treatments in 11 patients for which they attained effective angiographic responses of more than 60% increase in arterial diameter in all patients and clinical improvement in the Glasgow coma scale or resolution of focal symptoms in 10 of 11 patients (91%) following IA infusion of 10 to 40 mg of nicardipine.³⁸ Linfante et al. showed similarly promising results, with angiographic vasospasm improvement in 95% of cases following 2 to 25 mg of IA nicardipine infusion in 22 patients with symptomatic vasospasm, 50% of whom were functionally independent at the time of discharge.³⁹ Although retreatment is required in some patients, the current literature and experience suggest that the duration of effect of nicardipine is favorable when compared to other IA agents.

The benefits of IA nicardipine infusions may also extend to the microvascular and parenchymal levels, which may not be evidenced by angiographic examination of larger proximal vessel vasospasm.⁴⁰ In terms of complications, modest reductions in blood pressure of between 17 and 23 mm Hg have been reported with the use of IA nicardipine, and vasopressor support may occasionally be needed.^38,^39,⁴¹

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