Neuroprotection in Subarachnoid Hemorrhage

Abstract

Despite advances in aneurysm ablation and the initial management of patients presenting with aneurysmal subarachnoid hemorrhage (aSAH), delayed cerebral ischemia remains a significant source of morbidity. Traditionally, delayed cerebral ischemia was felt to be a result of vasospasm of the proximal intracranial vessels, and clinical trials have relied largely on radiographic evidence of vasospasm as a surrogate for functional outcome. However, a number of trials have demonstrated a dissociation between angiographic vasospasm and outcome, and more recent data suggests that other mechanisms of injury, such as microvascular dysfunction and complex neuronal-glial interactions may influence the development of delayed ischemic deficit following aSAH. Our evolving understanding of the pathophysiology of delayed cerebral ischemia may offer the opportunity to test new therapeutic strategies in this area and improve clinical trial design.

Introduction

Although aneurysmal subarachnoid hemorrhage (aSAH) accounts for less than 5% of all strokes, it represents a disproportionate source of morbidity and mortality, as afflicted individuals tend to be younger and often have worse outcome than those with ischemic stroke ^1–4. A significant proportion of the mortality associated with aSAH occurs soon after ictus, and in recent years, considerable advances have been made in the initial diagnosis and management of ruptured aneurysms, which has resulted in improved survival in hospitalized patients ⁵. For example, noninvasive imaging techniques such as MR and CT angiography have become increasingly sensitive at detecting aneurysms in the cerebral vasculature. Rebleeding is associated with an extremely high mortality, and current practice at most institutions is in favor of early aneurysm ablation, which is consistent with the results of a large trial on the timing of aneurysm surgery ². Endovascular techniques have also advanced rapidly and become widely adopted, facilitating the early ablation of aneurysms in patients that might otherwise have been considered poor operative risks.

Despite these advances, patients remain at considerable risk for neurological and medical complications following aneurysm ablation. In particular, subacute neurological deterioration due to delayed cerebral ischemia (DCI) remains one of the most feared complications associated with neurological morbidity. Traditionally, DCI was believed to be primarily due to vasospasm of the proximal cerebral vasculature, and luminal narrowing on conventional angiography may be present in up to two thirds of patients ⁶. Although smooth muscle contraction may play an important role in contributing to luminal narrowing, the term “vasospasm” itself may be an oversimplification, as preclinical and clinical studies have suggested morphological changes in the vasculature, including smooth muscle and endothelial proliferation ^7–9.

Because vascular changes and luminal narrowing may be dramatic on angiography, it would seem intuitive that vasospasm is the cause of DCI, and in fact these terms have been used interchangeably in the older literature. However, it is worth noting that an imperfect correlation exists between angiographic vasospasm and DCI ¹⁰. For example, only a subset of patients with angiographic vasospasm will manifest clinical symptoms of delayed ischemic deficit, and of these patients, not all will have clinical symptoms referable to the involved vascular distribution ¹¹. Similarly, although up to half of patients with delayed ischemic deficits will develop cerebral infarction, the area of infarct often does not correlate with the territory of angiographic vasospasm, and may appear pathologically as scattered laminar cortical and subortical infarcts rather than large vessel stroke ^12–14. Moreover, not all clinically symptomatic patients will have angiographic evidence of vasospasm; this is presumably due to involvement of smaller vessels that are not adequately imaged. Thus, although angiographic vasospasm is certainly correlated and likely contributes to DCI, infarct, and poor outcome, an argument may be made that it is as much a marker for a more diffuse microvascular disease rather than the proximal cause of all delayed ischemia¹².

Rethinking angiographic vasospasm as a primary outcome for therapeutic trials

Despite a number of clinical trials, little progress has been mad either in the pharmacological prophylaxis or treatment of DCI, nor in improving long term functional outcomes associated with this complication (Table 1). At present, the only pharmacological treatment that has been demonstrated to modestly improve outcome after aSAH is nimodipine, a dihydropyridine-type calcium channel blocker ¹⁵. Although the original rationale for the use of nimodipine was to reduce vasospasm by blocking calcium influx into vascular smooth muscle, there was no clear effect on angiographic vasospasm despite improvement in functional outcome ^{15, 16}. Thus, its mechanism of action remains controversial, and may be due, in part, to direct neuroprotective effects. Interestingly, nicardipine, a calcium channel blocker with a similar mechanism of action, demonstrated improvement in angiographic vasospasm, but did not demonstrate improvement in functional outcome ¹⁷. Thus, although nimodipine remains the only drug associated with improved outcomes, neither nimodipine nor any other calcium channel blocker has provided evidence that improvement in radiographic vasospasm is associated with improved functional outcome. Nonetheless, at many institutions, the transient improvement in radiographic vasospasm guides the use of intra-arterial administration of nicardipine and other smooth muscle relaxants, despite the lack of evidence that this strategy improves long term outcomes ^{18, 19}.

Table 1.

A truncated summary of major therapeutic trials designed to reduce delayed cerebral ischemia. A number of trials do not show a correlate between vasospasm and clinical outcome.

Intervention	n	Vasospasm Surrogate	Functional Outcome	Reference
Nimodipine	125	No benefit	Improved outcome	61
Nimodipine	154	No benefit	Improved outcome	15
Nimodipine	554	No benefit	Improved outcome	16
Nicardipine	906	Reduced vasospasm	No improvement	17
ET (A/B) antagonist (TAK-044)	420		No improvement	62
ET A antagonist (clazosentan)	32	Improved vasospasm		25
ET A antagonist (clozasentan)	413	Improved vasospasm	No improvement	26
Magnesium	113		No improvement	63
Magnesium	60		No improvement	22
Magnesium	283	Improved vasospasm	Improved outcome	64
Magnesium	40	No benefit		65
Magnesium	327		No benefit	21
Statin (simvastatin)	39	Reduced vasospasm		66
Statin (pravastatin)	80	Reduced vasospasm	Lower mortality	67
Statin (simvastatin)	39	No effect	No effect	68
Statin (simvastatin)	32	No effect	No effect	69
Aspirin	161	No improvement DIND		39
Aspirin	50		No improvement	37
Enoxaparin	117	No less TCD spasm		40
Enoxaparin	170		No improvement	38
Tirilazad	819	Improved vasospasm	No improvement	70
Tirilazad	823	No benefit	No improvement	71
Tirilazad	897	No benefit	No improvement	72
Tirilazad	1015	No benefit	No improvement	73

Although the majority of therapeutic trials have tested interventions designed to directly target the cerebral vasculature to reduce vasospasm, several neuroprotective strategies have also been tested. In general, these studies have also demonstrated dissociation between angiographic vasospasm and functional outcomes. For example, a recent meta-analysis of tirilizad, a nonglucocorticoid 21-aminosteroid designed to reduce lipid peroxidation, demonstrated a reduction in vasospasm, but no improvement in clinical outcomes as assessed by the Glascow Outcome Score ²⁰. In addition to its vasoactive properties, magnesium also has several potentially protective mechanisms of action following aSAH, including blockade of the N-methyl-D-aspartate–glutamate receptor and voltage-dependent calcium channels; however clinical trials have remained inconclusive^21–23.

More recently, therapeutic trials have targeted endothelin, an endogenous mediator of vasoconstriction that is believed to play an important role in vasospasm ²⁴. Based on early clinical work suggesting that clazosentan, an endothelin receptor A antagonist, reduced angiographic vasospasm ²⁵, a larger phase 2b study (CONSCIOUS-1), was initiated. The CONSCIOUS 1 trial confirmed that clazosentan improved the primary endpoint of angiographic vasospasm in a dose-dependent fashion. However, once again, despite an improvement in this angiographic endpoint, there was no associated improvement in functional outcomes ²⁶.

Thus, a dissociation between proximal vascular changes identified by angiography and improvement in functional outcomes has been demonstrated in a number of clinical and preclinical ²⁷ studies. Clearly, a surrogate endpoint that is mechanistically related to DCI and predictive of outcome is appealing for early clinical trials and would address the prohibitively large sample sizes that would be necessary if functionally relevant endpoints were used ²⁸. However, the poor track record of angiographic vasospasm might call into question its appropriateness as a primary surrogate endpoint predictive of functional outcome ^{11, 29–31}.

Other causes of treatable injury amenable to targeted treatment

In addition to the vascular changes associated with DCI, there are a number of other mechanisms of brain injury after aSAH that might be amenable to specific therapeutic interventions. For example, aneurysmal rupture is associated with acute brain injury due to mechanical compression of brain tissue, and secondary ischemia due to the hypoperfusion associated with increased intracranial pressures ³². These early destructive events may be mitigated by early management of intracranial hypertension, and administration of therapies designed to interrupt the ischemic cascade of excitotoxicity and neuronal calcium influx. Although conventional angiographic techniques have focused on the proximal cerebral vessels, there is increasing evidence of microvascular dysfunction ³³, which is suggested by the pattern of infarcts observed in some cases ^{12, 34}. Endothelial dysfunction, platelet aggregration, microthrombosis, and microembolization have been described and suggested as a possible basis for DCI ^{4, 12, 35, 36}. Although microembolization has been postulated as a mechanism of injury, trials of antiplatelet and anticoagulant therapies such as aspirin and enoxaparin have met with limited sucess ^37–40.

One of the interesting mechanisms of delayed cerebral injury that has gained increasing attention is cortical spreading depression (CSD). CSD refers to a wave of mass neuronal depolarization ⁴¹, and has been described in a variety of acute brain injury paradigms ^42–44. The normal physiological vascular response in the setting of CSD is vasodilation and hyperemia (Figure 1) ⁴⁵. However, in the setting of brain injuries such as subarachnoid hemorrhage, a paradoxical vasoconstriction may be observed ⁴⁶. This process, termed cortical spreading ischemia (CSI), is believed to be the result of inverse coupling between neuronal and astroglial interaction with cerebral blood flow ^{47, 48}. Although the exact mechanisms have not been fully defined, experimental evidence suggests that endothelin-1, which is upregulated after SAH, is a potent inducer of CSD⁴⁹, and reduces Na+/K+ ATPase activity ⁵⁰. In situations of decreased nitric oxide (NO), such as may occur in the presence of oxyhemoglobin, the normal physiological vasodilation is converted to vasoconstriction ⁴⁷, which may exacerbate secondary neuronal injury in vulnerable areas of brain ^{46, 48}. There are several observations that suggest that cortical spreading ischemia may be a clinically relevant phenomena following aSAH. For example, cortical spreading ischemia has been demonstrated to produce laminar cortical infarcts similar to that seen in autopsy studies of patients with DCI ^{12, 34, 47}. Moreover, recent clinical observations have confirmed episodes of cortical spreading ischemia in patients with SAH using electrocorticography and perfusion monitoring ⁴⁴. In many instances, these observed depolarization and perfusion changes were associated with clinical worsening characteristic of DCI. Interestingly, although cortical spreading depression may not be considered a primary vascular event, calcium channel blockers, such as nimodipine, have been demonstrated to partially block cortical spreading ischemia and reinstate a more physiological hyperemic response ⁴⁹. However, these effects may occur in smaller vessels, and thus resolution of angiographic vasospasm may not be the most appropriate surrogate.

Figure 1.

Following SAH, mediators of inflammation, including endothelin may initiate mass neuronal depolarization. In the presence of decreased availability of nitric oxide, an inverse coupling between neuronal and astroglial interaction with cerebral blood flow may resulting in spreading ischemia.

Clinical Implications

A more complete understanding of the mechanisms that contribute to DCI may have direct therapeutic and clinical research implications. For example, in addition to vasoactive therapies that target vasospasm, novel strategies that target neuronal and glial function may also hold promise. A recent report has demonstrated that administration of levetiracetam, an anticonvulsant that targets a presynaptic neuronal vesicular protein, reduces vasospasm and histological injury, and improves functional outcomes in a murine model of subarachnoid hemorrhage ⁵¹. Similarly, a therapeutic peptide derived from the apolipoprotein E protein, which modulates glial activation and reduces glutamate excitotoxicity, has also demonstrated promise in murine SAH models ^{27, 52}. Although traditional neuroprotective strategies that target glutamate excitotoxicity and oxidative stress have been difficult to translate to clinical trials of acute stroke, they may have potential in reducing DCI, as drug can be started prior to onset of ischemic symptoms in a tightly controlled setting.

In addition to suggesting new therapeutic targets, an increased understanding of the pathophysiology of DCI may also have implications for post-operative management strategies in the care of at-risk patients. Understanding the real-time effects of therapeutic interventions such as manipulating hemodynamics or oxygenation is facilitated by the fact that multimodal monitoring, including parenchymal oximetry, is now widely available at many institutions. For example, in experimental models, hyperoxia may reduce CSD, and a recent clinical study has demonstrated that clusters of CSD are associated with local tissue hypoxia ⁴². This demonstrates the importance of monitoring and optimizing tissue oxygen pressures through hemodynamic control and ventilator management. Similarly, although hyperglycemia has been associated with poor outcome following SAH ⁵³, recent prospective trials of tight glucose control in aSAH have been mixed ^{54, 55}. Hyperglycemia may in fact attenuate CSD ⁵⁶, and overly aggressive glycemic control increases the risk for episodes of hypoglycemia which might exacerbate tissue injury ⁵⁷.

Given the seemingly obvious causal relationship between vascular changes observed on angiography and DCI, most therapeutic trials have relied on angiographic surrogates of vasospasm. As noted above, however, the majority of clinical trials have demonstrated dissociation between angiographic vasospasm and functional outcome. A more complete understanding of the role that microvascular dysfunction and CSI plays in contributing to secondary neurological deterioration would also suggest the importance of incorporating more global measures of diffuse brain injury and neurocognitive dysfunction into clinical trials ^{58, 59}, rather than focusing primarily on proximal vasospasm and large vessel stroke.

The role of neuroprotectants in SAH: Broader implications for stroke

Ultimately the testing of neuroprotectant strategies in the setting of subarachnoid hemorrhage may have broad implications for trials of acute stroke and cerebrovascular disease. Traditionally, stroke trials have been difficult to perform for a number of reasons ⁶⁰, including initiating therapy soon enough after symptom onset for a neuroprotective agent to be effective. The historical failure of stroke neuroprotection trials, coupled with the expense and logistic difficulties associated with these trials, has led to an unfortunate reduction in enthusiasm for acute stroke research. However, patients with aSAH in the neurocritical care unit may offer a number of advantages for early trials in cerebrovascular disease. Aneurysmal SAH is one of the few situations in which cerebral ischemia occurs in a reproducible and delayed time frame, allowing patients to be enrolled and drug started prior to the onset of ischemia. Moreover, unlike most acute stroke trials, aSAH trials take place in a controlled setting, and trials can be enriched for patients likely to experience DCI by selecting those with large subarachnoid clot burden. Thus, testing for neuroprotection in aSAH may ultimately be an ideal way to provide proof-of-concept data prior to testing an agent for neuroprotection in acute ischemic stroke.